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Zhao H, Zhang Y, Sun Y, Zhu Z, Ren J, Qu X. Self-Driven CuAAC Reaction Catalyzed by Photosensitive Biohybrids Energized by Lactate for Boosting Cancer Immunotherapy. Angew Chem Int Ed Engl 2025; 64:e202425018. [PMID: 39973575 DOI: 10.1002/anie.202425018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 02/21/2025]
Abstract
As a typical bioorthogonal reaction, the copper (I) catalyzed azide-alkyne 1,3-cycloaddition (CuAAC) reaction strongly depends on the reducing agents and the rate of the CuAAC reaction is far from sufficient to produce drug agents under physiological conditions. It is necessary and highly demanding to develop an efficient CuAAC reaction without using chemical reducing agents. Herein, inspired by the extracellular electron transfer (EET) mechanisms of the electroactive bacteria within the realm of synthetic biology, a photo-assisted targeting electroactive bacteria equipped bioorthogonal catalyst system for boosting cancer immunotherapy is constructed. The bacteria specifically anaerobically catabolize lactate at the tumor site, accompanied by transferring electrons to the bioorthogonal catalyst, thereby triggering the CuAAC reaction to produce active drugs in situ. Strikingly, under illumination, the photoelectrons generated by attached AuNPs can be transported into bacterial cytoplasm to accelerate the CuAAC reaction by promoting cellular metabolism. The biohybrid enables synergistic immunogenic cell death (ICD), immune checkpoint blockade (ICB) immunotherapy and alleviation of immunosuppressive microenvironment. Ingeniously, ICD and lactate consumption both boost the efficacy of ICB immunotherapy. Overall, the system provides a bridge between the tumor metabolism and CuAAC reaction through bacterial respiration, offering fascinating opportunities for controlled synthesis of active molecules by bioorthogonal catalysis.
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Affiliation(s)
- Huisi Zhao
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Yu Zhang
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Yue Sun
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Zitong Zhu
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Jinsong Ren
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
| | - Xiaogang Qu
- Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China
- University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China
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2
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Li L, Chen M, Reis RL, Kundu SC, Xiao B, Shi X. Advancements of nanoscale drug formulations for combination treatment of colorectal cancer. Int J Pharm 2025; 674:125508. [PMID: 40132771 DOI: 10.1016/j.ijpharm.2025.125508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 03/27/2025]
Abstract
Combination chemotherapy is widely utilized in treating colorectal cancer (CRC), particularly for patients who are ineligible for surgery or those with metastatic CRC (mCRC). While this therapeutic method has demonstrated efficacy in managing CRC and mCRC, its broader clinical application is limited due to the unique physical properties, mechanisms of action, and pharmacokinetics of different chemotherapeutic drugs. Consequently, achieving satisfactory treatment outcomes proves to be challenging. Nanotechnology has given rise to innovative drug systems that are precise, controllable, and highly efficient in drug delivery. These nanoscale drug delivery systems can integrate the advantageous aspects of various therapeutic modalities, including chemotherapy, gene therapy, and immunotherapy. This review aims to explain the application of nano-drug delivery system in the treatment of colorectal cancer. Through its unique physical/chemical properties and biological functions, it can solve the limitations of traditional therapy and achieve more accurate, efficient and safe treatment. The advantages/disadvantages, physical and chemical characteristics of various drug delivery systems are described in detail, and suggestions on selecting reasonable NDDSs according to different drug combination methods are given to achieve the best therapeutic effect. This review paper presents an exhaustive summary of the diverse range of drugs utilized in chemotherapy, in addition to outlining strategies for effectively integrating chemotherapy with other treatment modalities. Furthermore, it delves into the principle of selecting carriers for various drug combinations.
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Affiliation(s)
- Liqi Li
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Maohua Chen
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Rui L Reis
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Bo Xiao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
| | - Xiaoxiao Shi
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Beibei, Chongqing 400715, China.
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3
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Biswal S, Sahoo SK, Biswal BK. Shikonin a potent phytotherapeutic: a comprehensive review on metabolic reprogramming to overcome drug resistance in cancer. Mol Biol Rep 2025; 52:347. [PMID: 40156720 DOI: 10.1007/s11033-025-10459-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
Drug resistance remains a major challenge in cancer therapy, often leading to treatment failure. Metabolic reprogramming, a hallmark of cancer, plays a pivotal role in drug resistance. Phytocompounds, particularly shikonin, a naphthoquinone derived from Lithospermum erythrorhizon, have garnered significant interest as potential alternatives for cancer prevention and treatment. This review focuses on the anticancer properties of shikonin, particularly its ability to modulate metabolic reprogramming and overcome drug resistance. This review, based on extensive searches in databases like PubMed, Web of Science, Google Scholar, and Scopus, highlights shikonin's potential as a therapeutic agent. Shikonin exhibits a wide range of anticancer activities, including induction of apoptosis, autophagy, necroptosis, inhibition of angiogenesis, invasion, and migration, as well as disruption of the cell cycle and promotion of DNA damage. It targets altered cancer cell metabolism to inhibit proliferation and reverse drug resistance, making it a promising candidate for therapeutic development. Preliminary clinical trials suggest that shikonin can enhance the efficacy of established chemotherapeutic agents, immunotherapies, and radiation through additive and synergistic interactions. Despite its promise, further research is needed to elucidate the precise mechanisms underlying shikonin's metabolic reprogramming effects in cancer. A comprehensive understanding could pave the way for its integration into standard oncological treatments. With its capacity to act on multiple cancer pathways and enhance conventional treatments, shikonin stands out as a viable candidate for combating drug-resistant cancers and advancing clinical oncology.
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Affiliation(s)
- Stuti Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha, 769008, India
| | | | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology, Rourkela, Odisha, 769008, India.
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4
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Pandey V, Pandey T. Mechanistic understanding of pH as a driving force in cancer therapeutics. J Mater Chem B 2025; 13:2640-2657. [PMID: 39878033 DOI: 10.1039/d4tb02083a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
The development of pH-directed nanoparticles for tumor targeting represents a significant advancement in cancer biology and therapeutic strategies. These innovative materials have the ability to interact with the unique acidic microenvironment of tumors. They enhance drug delivery, increase therapeutic efficacy, and reduce systemic toxicity. The acidic conditions within tumors trigger the release of drugs from pH-responsive nanoparticles, ensuring targeted and controlled delivery directly to cancer cells while minimizing damage to healthy tissues. This review comprehensively explores the design, synthesis, and application of pH-stabilized nanoparticles in cancer therapy. It delves into the mechanisms of pH-responsive behavior, such as the use of pH-sensitive polymers and cleavable linkages that respond to the acidic tumor environment. Current strategies for nanoparticle stabilization, including surface coating, core-shell nanostructures, and hybrid nanoparticles, are discussed in detail, highlighting how these approaches enhance the stability and functionality of the nanoparticles in biological systems. Recent advancements in nanoparticle-based drug delivery systems are examined, showcasing multi-functional nanoparticles that combine therapeutic and diagnostic functions, as well as those designed for combination therapy to overcome drug resistance. This review identifies future directions in the field, such as the need for improved stability and biocompatibility, controlled and predictable drug release, and overcoming regulatory and manufacturing hurdles. Herein, we have highlighted the transformative potential of pH-stabilized nanoparticles in cancer therapy, offering a pathway towards more effective and targeted cancer treatments.
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Affiliation(s)
- Vivek Pandey
- Department of Chemistry, School for Chemical engineering and Physical Sciences, Lovely Professional University, Phagwara, Punjab, India.
| | - Tejasvi Pandey
- Department of Forensic Science, School for Bio Engineering and Bio Sciences, Lovely Professional University, Phagwara, Punjab, India
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He A, Liao F, Lin X. Circ_0007351 Exerts an Oncogenic Role In Colorectal Cancer Depending on the Modulation of the miR-5195-3p/GPRC5A Cascade. Mol Biotechnol 2025; 67:617-627. [PMID: 38386274 DOI: 10.1007/s12033-024-01071-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/08/2024] [Indexed: 02/23/2024]
Abstract
Circular RNAs (circRNAs) exert critical functions in colorectal cancer development. In this work, we wanted to elucidate the functional role and regulatory mechanism of circ_0007351 in colorectal cancer. For quantification of circ_0007351, microRNA (miR)-5195-3p and G Protein-coupled receptor class C group 5 member A (GPRC5A), a qRT-PCR, immunoblotting or immunohistochemistry assay was performed. Effects of circ_0007351/miR-5195-3p/GPRC5A cascade were evaluated by determining cell viability, proliferation, colony formation, motility, and invasion. Relationships among variables were assessed by dual-luciferase reporter assay. Animal studies were performed to evaluate circ_0007351's function in the growth of xenograft tumors. Circ_0007351 was markedly up-regulated in colorectal cancer tissues and cells. Down-regulation of circ_0007351 hindered cell growth, migration and invasiveness. Also, circ_0007351 depletion exerted a suppressive function in colorectal cell xenograft growth in vivo. Mechanistically, circ_0007351 sponged miR-5195-3p to sequester miR-5195-3p. Reduction of available miR-5195-3p neutralized the effects of circ_0007351 down-regulation on cell phenotypes. MiR-5195-3p directly targeted and inhibited GPRC5A. Circ_0007351 regulated GPRC5A expression by sponging miR-5195-3p. Moreover, the effects of circ_0007351 down-regulation on cell functional phenotypes were due to in part the reduction of GPRC5A expression. Our findings show that circ_0007351 down-regulation impedes proliferation, motility, and invasiveness in colorectal cancer cells at least in part via the regulation of the miR-5195-3p/GPRC5A cascade, highlighting that circ_0007351 inhibition may have a potential therapeutic value for colorectal cancer.
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Affiliation(s)
- Aijun He
- Oncology Department, People's Hospital of Shenzhen Baoan District, NO. 118, Longjing Road, Baoan District, Shenzhen, 518100, China
| | - Fangxin Liao
- Oncology Department, People's Hospital of Shenzhen Nanshan, Shenzhen, 518100, China
| | - Xiaohui Lin
- Oncology Department, People's Hospital of Shenzhen Baoan District, NO. 118, Longjing Road, Baoan District, Shenzhen, 518100, China.
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6
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Dou L, Fang Y, Yang H, Ai G, Shen N. Immunogenic cell death: A new strategy to enhancing cancer immunotherapy. Hum Vaccin Immunother 2024; 20:2437918. [PMID: 39655738 PMCID: PMC11639453 DOI: 10.1080/21645515.2024.2437918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 11/14/2024] [Accepted: 12/02/2024] [Indexed: 12/15/2024] Open
Abstract
Immunogenic cell death (ICD) is a distinct type of stress-induced regulated cell death that can lead to adaptive immune responses and the establishment of immunological memory. ICD exhibits both similarities and differences when compared to apoptosis and other non-apoptotic forms of regulated cell death (RCD). The interplay between ICD-mediated immunosurveillance against cancer and the ability of cancer cells to evade ICD influences the host-tumor immunological interaction. Consequently, the restoration of ICD and the development of effective strategies to induce ICD have emerged as crucial considerations in the treatment of cancer within the context of immunotherapy. To enhance comprehension of ICD in the setting of cancer, this paper examines the interconnected responsive pathways associated with ICD, the corresponding biomarkers indicative of ICD, and the mechanisms through which tumors subvert ICD. Additionally, this review explores strategies for reinstating ICD and the therapeutic potential of harnessing ICD in cancer immunotherapy.
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Affiliation(s)
- Lei Dou
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Fang
- Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiyuan Yang
- Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guo Ai
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Na Shen
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Kedir WM, Li L, Tan YS, Bajalovic N, Loke DK. Nanomaterials and methods for cancer therapy: 2D materials, biomolecules, and molecular dynamics simulations. J Mater Chem B 2024; 12:12141-12173. [PMID: 39502031 DOI: 10.1039/d4tb01667j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
This review explores the potential of biomolecule-based nanomaterials, i.e., protein, peptide, nucleic acid, and polysaccharide-based nanomaterials, in cancer nanomedicine. It highlights the wide range of design possibilities for creating multifunctional nanomedicines using these biomolecule-based nanomaterials. This review also analyzes the primary obstacles in cancer nanomedicine that can be resolved through the usage of nanomaterials based on biomolecules. It also examines the unique in vivo characteristics, programmability, and biological functionalities of these biomolecule-based nanomaterials. This summary outlines the most recent advancements in the development of two-dimensional semiconductor-based nanomaterials for cancer theranostic purposes. It focuses on the latest developments in molecular simulations and modelling to provide a clear understanding of important uses, techniques, and concepts of nanomaterials in drug delivery and synthesis processes. Finally, the review addresses the challenges in molecular simulations, and generating, analyzing, and developing biomolecule-based and two-dimensional semiconductor-based nanomaterials, and highlights the barriers that must be overcome to facilitate their application in clinical settings.
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Affiliation(s)
- Welela M Kedir
- Department of Science, Mathematics and Technology, Singapore University of Technology and Design, Singapore 487372, Singapore.
| | - Lunna Li
- Thomas Young Centre and Department of Chemical Engineering, University College London, London WC1E 7JE, UK
| | - Yaw Sing Tan
- Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
| | - Natasa Bajalovic
- Department of Science, Mathematics and Technology, Singapore University of Technology and Design, Singapore 487372, Singapore.
| | - Desmond K Loke
- Department of Science, Mathematics and Technology, Singapore University of Technology and Design, Singapore 487372, Singapore.
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8
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Chen J, Liu J, Nie W, Hou X, Zhang X, Liu C, Si L, Zhang M, Xu S, Xie Q, Liang J, Li Y. Research progress on the structural and anti-colorectal malignant tumor properties of Shikonin. J Cancer Res Ther 2024; 20:1957-1963. [PMID: 39792404 DOI: 10.4103/jcrt.jcrt_933_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/17/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACT Colorectal cancer is the third most prevalent malignant tumor worldwide. Despite the advancements in surgical procedures and treatment options, CRC remains a considerable cause of cancer-related mortality. Shikonin is a naphthoquinone compound that exhibits multiple biological activities, including anti-inflammatory and anti-tumor effects as well as wound healing promotion. Recently, Shikonin has been increasingly used in basic research on colorectal malignant tumors. Therefore, we explored the mechanisms of action and structural improvements of Shikonin in colorectal cancer through a literature review to provide valuable insights for the advancement of research and development of related pharmaceuticals.
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Affiliation(s)
- Jinghua Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Jie Liu
- Department of Pediatric Intensive Care Unit, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Weiwei Nie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Xingqin Hou
- South Ward, The Second Hospital of Shandong University, Jinan, China
| | - Xi Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Chao Liu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Linxin Si
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Mingzhu Zhang
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Shutao Xu
- Department of Oncology, People's Hospital of Zhangdian District, Zibo, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Yan Li
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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Hani U, Choudhary VT, Ghazwani M, Alghazwani Y, Osmani RAM, Kulkarni GS, Shivakumar HG, Wani SUD, Paranthaman S. Nanocarriers for Delivery of Anticancer Drugs: Current Developments, Challenges, and Perspectives. Pharmaceutics 2024; 16:1527. [PMID: 39771506 PMCID: PMC11679327 DOI: 10.3390/pharmaceutics16121527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/06/2024] [Accepted: 11/16/2024] [Indexed: 01/11/2025] Open
Abstract
Cancer, the most common condition worldwide, ranks second in terms of the number of human deaths, surpassing cardiovascular diseases. Uncontrolled cell multiplication and resistance to cell death are the traditional features of cancer. The myriad of treatment options include surgery, chemotherapy, radiotherapy, and immunotherapy to treat this disease. Conventional chemotherapy drug delivery suffers from issues such as the risk of damage to benign cells, which can cause toxicity, and a few tumor cells withstand apoptosis, thereby increasing the likelihood of developing tolerance. The side effects of cancer chemotherapy are often more pronounced than its benefits. Regarding drugs used in cancer chemotherapy, their bioavailability and stability in the tumor microenvironment are the most important issues that need immediate addressing. Hence, an effective and reliable drug delivery system through which both rapid and precise targeting of treatment can be achieved is urgently needed. In this work, we discuss the development of various nanobased carriers in the advancement of cancer therapy-their properties, the potential of polymers for drug delivery, and recent advances in formulations. Additionally, we discuss the use of tumor metabolism-rewriting nanomedicines in strengthening antitumor immune responses and mRNA-based nanotherapeutics in inhibiting tumor progression. We also examine several issues, such as nanotoxicological studies, including their distribution, pharmacokinetics, and toxicology. Although significant attention is being given to nanotechnology, equal attention is needed in laboratories that produce nanomedicines so that they can record themselves in clinical trials. Furthermore, these medicines in clinical trials display overwhelming results with reduced side effects, as well as their ability to modify the dose of the drug.
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Affiliation(s)
- Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia; (U.H.); (M.G.)
| | - Vikram T. Choudhary
- Department of Pharmaceutics, The Oxford College of Pharmacy, Hongsandra, Bengaluru 560068, India;
| | - Mohammed Ghazwani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia; (U.H.); (M.G.)
| | - Yahia Alghazwani
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia;
| | - Riyaz Ali M. Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru 570015, India; (R.A.M.O.); (H.G.S.)
| | - Gururaj S. Kulkarni
- Department of Pharmaceutics, The Oxford College of Pharmacy, Hongsandra, Bengaluru 560068, India;
| | - Hosakote G. Shivakumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSS AHER), Mysuru 570015, India; (R.A.M.O.); (H.G.S.)
| | - Shahid Ud Din Wani
- Department of Pharmaceutical Sciences, School of Applied Sciences and Technology, University of Kashmir, Srinagar 190006, India;
| | - Sathishbabu Paranthaman
- Department of Cell Biology and Molecular Genetics, Sri Devraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research, Kolar 563103, India;
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10
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Xie Q, Liu X, Liu R, Pan J, Liang J. Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer. Mol Cancer 2024; 23:252. [PMID: 39529058 PMCID: PMC11555832 DOI: 10.1186/s12943-024-02166-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.
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Affiliation(s)
- Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China
| | - Xiaolin Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China
| | - Rengyun Liu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jingxuan Pan
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
| | - Jing Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, 250014, China.
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11
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Shahzad A, Teng Z, Yameen M, Liu W, Cui K, Liu X, Sun Y, Duan Q, Xia J, Dong Y, Bai Z, Peng D, Zhang J, Xu Z, Pi J, Yang Z, Zhang Q. Innovative lipid nanoparticles: A cutting-edge approach for potential renal cell carcinoma therapeutics. Biomed Pharmacother 2024; 180:117465. [PMID: 39321512 DOI: 10.1016/j.biopha.2024.117465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024] Open
Abstract
The kidney plays a crucial role in regulating homeostasis within the human body. Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for nearly 90 % of all renal malignancies. Despite the availability of various therapeutic strategies, RCC remains a challenging disease due to its resistance to conventional treatments. Nanotechnology has emerged as a promising field, offering new opportunities in cancer therapeutics. It presents several advantages over traditional methods, enabling diverse biomedical applications, including drug delivery, prevention, diagnosis, and treatment. Lipid nanoparticles (LNPs), approximately 100 nm in size, are derived from a range of lipids and other biochemical compounds. these particulates are designed to overcome biological barriers, allowing them to selectively accumulate at diseased target sites for effective therapeutic action. Many pharmaceutically important compounds face challenges such as poor solubility in aqueous solutions, chemical and physiological instability, or toxicity. LNP technology stands out as a promising drug delivery system for bioactive organic compounds. This article reviews the applications of LNPs in RCC treatment and explores their potential clinical translation, identifying the most viable LNPs for medical use. With ongoing advancement in LNP-based anticancer strategies, there is a growing potential to improve the management and treatment of renal cancer.
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Affiliation(s)
- Asif Shahzad
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhuoran Teng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Muhammad Yameen
- Department of Biochemistry, Government College University Faisalabad, Punjab 38000, Pakistan
| | - Wenjing Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Kun Cui
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xiangjie Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yijian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Qiuxin Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - JiaoJiao Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yurong Dong
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Ziyuan Bai
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Dongmei Peng
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Jinshan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhe Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China.
| | - Zhe Yang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China.
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12
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Liang J, Tian X, Zhou M, Yan F, Fan J, Qin Y, Chen B, Huo X, Yu Z, Tian Y, Deng S, Peng Y, Wang Y, Liu B, Ma X. Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death. Biomaterials 2024; 309:122608. [PMID: 38744189 DOI: 10.1016/j.biomaterials.2024.122608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 04/21/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024]
Abstract
Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.
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Affiliation(s)
- Jiahao Liang
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China; Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Xiangge Tian
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Meirong Zhou
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China; Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Fei Yan
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jialong Fan
- College of Biology, Hunan University, Changsha, China
| | - Yan Qin
- College of Biology, Hunan University, Changsha, China
| | - Binlong Chen
- College of Biology, Hunan University, Changsha, China
| | - Xiaokui Huo
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Zhenlong Yu
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China; Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China.
| | - Yan Tian
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Sa Deng
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Yulin Peng
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Yan Wang
- Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Integrative Medicine, College of Pharmacy, Dalian Medical University, Dalian, China
| | - Bin Liu
- College of Biology, Hunan University, Changsha, China.
| | - Xiaochi Ma
- Pharmaceutical Research Center, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
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13
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Li T, Zhang L. Autophagy-related biomarkers in hepatocellular carcinoma and their relationship with immune infiltration. Discov Oncol 2024; 15:299. [PMID: 39042294 PMCID: PMC11266335 DOI: 10.1007/s12672-024-01167-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND Autophagy regulation plays vital roles in many cancers. We aimed to investigate the expression, prognostic value, and immune infiltration of autophagy-related genes in hepatocellular carcinoma (HCC) by bioinformatics analysis. METHOD Human autophagy-related differentially expressed genes (DEGs) between adjacent and HCC tissues were identified. We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We also evaluated immune infiltration and the response to tumor-sensitive drugs. Finally, we verified the expression of these proteins in clinical samples by immunohistochemistry (IHC), RNA isolation and real-time reverse transcription polymerase chain reaction (RT‒PCR). RESULTS A total of 57 autophagy-related DEGs were identified. The HUB genes (BIRC5, CDKN2A, SPP1, and IGF1) were related to the diagnosis and prognosis of HCC. The HUB genes were significantly enriched in immune-related pathways. Furthermore, correlation analysis revealed that HUB gene expression was associated with immune infiltration. We identified 35 tumor-sensitive drugs targeting the HUB genes. Finally, by IHC, we discovered that the protein of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues; by RT‒PCR, we discovered that the mRNA of CDKN2A, BIRC5, and SPP1 were upregulated in HCC tissues, while the mRNA of IGF1 was downregulated in HCC tissues compared with the levels in paracarcinoma tissues. CONCLUSION We screened and validated four autophagy-related genes associated with immune infiltration and prognosis in patients with HCC.
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Affiliation(s)
- Tingting Li
- Clinical Laboratory Department, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lin Zhang
- Clinical Laboratory Department, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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14
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Elzoghby AO, Samir O, Emam HE, Soliman A, Abdelgalil RM, Elmorshedy YM, Elkhodairy KA, Nasr ML. Engineering nanomedicines for immunogenic eradication of cancer cells: Recent trends and synergistic approaches. Acta Pharm Sin B 2024; 14:2475-2504. [PMID: 38828160 PMCID: PMC11143780 DOI: 10.1016/j.apsb.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 02/07/2024] [Accepted: 03/09/2024] [Indexed: 06/05/2024] Open
Abstract
Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment (TME) leading to failure of immune response. Numerous therapeutic strategies including chemotherapy, radiotherapy, photodynamic, photothermal, magnetic, chemodynamic, sonodynamic and oncolytic therapy, have been developed to induce immunogenic cell death (ICD) of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response. However, many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response. Here, we outline the current state of using nanomedicines for boosting ICD of cancer cells. Moreover, synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints, phagocytosis, macrophage polarization, tumor hypoxia, autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed. We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses. Endoplasmic reticulum localized ICD, focused ultrasound hyperthermia, cell membrane camouflaged nanomedicines, amplified reactive oxygen species (ROS) generation, metallo-immunotherapy, ion modulators and engineered bacteria are among the most innovative approaches. Various challenges, merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.
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Affiliation(s)
- Ahmed O. Elzoghby
- Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
| | - Omar Samir
- Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
| | - Hagar E. Emam
- Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
| | - Ahmed Soliman
- Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
| | - Riham M. Abdelgalil
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Yomna M. Elmorshedy
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Kadria A. Elkhodairy
- Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
| | - Mahmoud L. Nasr
- Division of Engineering in Medicine and Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, MA, USA
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15
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Choi Y, Seok SH, Yoon HY, Ryu JH, Kwon IC. Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade. Adv Drug Deliv Rev 2024; 209:115306. [PMID: 38626859 DOI: 10.1016/j.addr.2024.115306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 05/23/2024]
Abstract
Cancer immunotherapy represents a revolutionary strategy, leveraging the patient's immune system to inhibit tumor growth and alleviate the immunosuppressive effects of the tumor microenvironment (TME). The recent emergence of immune checkpoint blockade (ICB) therapies, particularly following the first approval of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors like ipilimumab, has led to significant growth in cancer immunotherapy. The extensive explorations on diverse immune checkpoint antibodies have broadened the therapeutic scope for various malignancies. However, the clinical response to these antibody-based ICB therapies remains limited, with less than 15% responsiveness and notable adverse effects in some patients. This review introduces the emerging strategies to overcome current limitations of antibody-based ICB therapies, mainly focusing on the development of small interfering ribonucleic acid (siRNA)-based ICB therapies and innovative delivery systems. We firstly highlight the diverse target immune checkpoint genes for siRNA-based ICB therapies, incorporating silencing of multiple genes to boost anti-tumor immune responses. Subsequently, we discuss improvements in siRNA delivery systems, enhanced by various nanocarriers, aimed at overcoming siRNA's clinical challenges such as vulnerability to enzymatic degradation, inadequate pharmacokinetics, and possible unintended target interactions. Additionally, the review presents various combination therapies that integrate chemotherapy, phototherapy, stimulatory checkpoints, ICB antibodies, and cancer vaccines. The important point is that when used in combination with siRNA-based ICB therapy, the synergistic effect of traditional therapies is strengthened, improving host immune surveillance and therapeutic outcomes. Conclusively, we discuss the insights into innovative and effective cancer immunotherapeutic strategies based on RNA interference (RNAi) technology utilizing siRNA and nanocarriers as a novel approach in ICB cancer immunotherapy.
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Affiliation(s)
- Youngjin Choi
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Su Hyun Seok
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
| | - Hong Yeol Yoon
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Ju Hee Ryu
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
| | - Ick Chan Kwon
- Medicinal Materials Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
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16
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Liu J, Wang T, Zhang W, Huang Y, Wang X, Li Q. Association between Metabolic Reprogramming and Immune Regulation in Digestive Tract Tumors. Oncol Res Treat 2024; 47:273-286. [PMID: 38636467 DOI: 10.1159/000538659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 03/28/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy.
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Affiliation(s)
- Jiafeng Liu
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Tianxiao Wang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenxin Zhang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxin Huang
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
| | - Xinhai Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Qunyi Li
- Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, China
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17
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Chen Y, Shu X, Guo JY, Xiang Y, Liang SY, Lai JM, Zhou JY, Liu LH, Wang P. Nanodrugs mediate TAMs-related arginine metabolism interference to boost photodynamic immunotherapy. J Control Release 2024; 367:248-264. [PMID: 38272398 DOI: 10.1016/j.jconrel.2024.01.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/31/2023] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L-arginine (L-Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L-norvaline (L-Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L-Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L-Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC.
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Affiliation(s)
- Yi Chen
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China
| | - Xian Shu
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China
| | - Jia-Yi Guo
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China
| | - Yun Xiang
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China
| | - Shi-Yu Liang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Jin-Mei Lai
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China
| | - Jia-Yi Zhou
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China
| | - Li-Han Liu
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China.
| | - Ping Wang
- Department of Ultrasonography, The Third Affiliated Hospital, The Third Clinical College, Southern Medical University, Guangzhou 510630, Guangdong Province, PR China.
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18
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Li X, Sun T, Jiang C. Intelligent Delivery Systems in Tumor Metabolism Regulation: Exploring the Path Ahead. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2309582. [PMID: 38105387 DOI: 10.1002/adma.202309582] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/07/2023] [Indexed: 12/19/2023]
Abstract
Cancer metabolism plays multifaceted roles in the initiation and progression of tumors, and interventions in metabolism are considered fundamental approaches for cancer control. Within the vast metabolic networks of tumors, there exist numerous potential therapeutic targets, intricately interconnected with each other and with signaling networks related to immunity, metastasis, drug resistance, and more. Based on the characteristics of the tumor microenvironment, constructing drug delivery systems for multi-level modulation of the tumor microenvironment is proven as an effective strategy for achieving multidimensional control of cancer. Consequently, this article summarizes several features of tumor metabolism to provide insights into recent advancements in intelligent drug delivery systems for achieving multi-level regulation of the metabolic microenvironment in cancer, with the aim of offering a novel paradigm for cancer treatment.
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Affiliation(s)
- Xuwen Li
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, 201203, China
| | - Tao Sun
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, 201203, China
| | - Chen Jiang
- Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai, 201203, China
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19
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Cheng Q, Shi X, Li Q, Wang L, Wang Z. Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305662. [PMID: 37941489 PMCID: PMC10797484 DOI: 10.1002/advs.202305662] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/15/2023] [Indexed: 11/10/2023]
Abstract
Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.
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Affiliation(s)
- Qian Cheng
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Xiao‐Lei Shi
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Qi‐Lin Li
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Lin Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Research Center for Tissue Engineering and Regenerative MedicineUnion HospitalHuazhong University of Science and TechnologyWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
| | - Zheng Wang
- Department of Clinical LaboratoryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
- Hubei Key Laboratory of Regenerative Medicine and Multi‐disciplinary Translational ResearchWuhan430022China
- Department of Gastrointestinal SurgeryUnion HospitalTongji Medical CollegeHuazhongUniversity of Science and TechnologyWuhan430022China
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20
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Sa P, Mohapatra P, Swain SS, Khuntia A, Sahoo SK. Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights. Mol Pharm 2023; 20:5254-5277. [PMID: 37596986 DOI: 10.1021/acs.molpharmaceut.3c00286] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/21/2023]
Abstract
Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.
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Affiliation(s)
- Pratikshya Sa
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
| | - Priyanka Mohapatra
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
| | | | - Auromira Khuntia
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad, Haryana 121001, NCR Delhi, India
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21
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Dong X, Xia S, Du S, Zhu MH, Lai X, Yao SQ, Chen HZ, Fang C. Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy. ACS CENTRAL SCIENCE 2023; 9:1864-1893. [PMID: 37901179 PMCID: PMC10604035 DOI: 10.1021/acscentsci.3c00702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Indexed: 10/31/2023]
Abstract
Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.
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Affiliation(s)
- Xiao Dong
- Department
of Pharmacy, School of Medicine, Shanghai
University, Shanghai 200444, China
| | - Shu Xia
- Department
of Pharmacy, School of Medicine, Shanghai
University, Shanghai 200444, China
| | - Shubo Du
- School
of Bioengineering, Dalian University of
Technology, Dalian 116024, China
| | - Mao-Hua Zhu
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
| | - Xing Lai
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
| | - Shao Q. Yao
- Department
of Chemistry, National University of Singapore, Singapore 117543, Singapore
| | - Hong-Zhuan Chen
- Institute
of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Chao Fang
- Hongqiao
International Institute of Medicine, Tongren Hospital and State Key
Laboratory of Systems Medicine for Cancer, Department of Pharmacology
and Chemical Biology, Shanghai Jiao Tong
University School of Medicine, Shanghai, 200025 China
- Key
Laboratory of Basic Pharmacology of Ministry of Education & Joint
International Research Laboratory of Ethnomedicine of Ministry of
Education, Zunyi Medical University, Zunyi 563003, China
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22
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Guo Y, Gao F, Ahmed A, Rafiq M, Yu B, Cong H, Shen Y. Immunotherapy: cancer immunotherapy and its combination with nanomaterials and other therapies. J Mater Chem B 2023; 11:8586-8604. [PMID: 37614168 DOI: 10.1039/d3tb01358h] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/25/2023]
Abstract
Immunotherapy is a new type of tumor treatment after surgery, radiotherapy and chemotherapy, and can be used to manage and destroy tumor cells through activating or strengthening the immune response. Immunotherapy has the benefits of a low recurrence rate and high specificity compared to traditional treatment methods. Immunotherapy has developed rapidly in recent years and has become a research hotspot. Currently, chimeric antigen receptor T-cell immunotherapy and immune checkpoint inhibitors are the most effective tumor immunotherapies in clinical practice. While tumor immunotherapy brings hope to patients, it also faces some challenges and still requires continuous research and progress. Combination therapy is the future direction of anti-tumor treatment. In this review, the main focus is on an overview of the research progress of immune checkpoint inhibitors, cellular therapies, tumor vaccines, small molecule inhibitors and oncolytic virotherapy in tumor treatment, as well as the combination of immunotherapy with other treatments.
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Affiliation(s)
- Yuanyuan Guo
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Fengyuan Gao
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Adeel Ahmed
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Muhammad Rafiq
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
| | - Bing Yu
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, Qingdao 266071, China
| | - Hailin Cong
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- State Key Laboratory of Bio-Fibers and Eco-Textiles, Qingdao University, Qingdao 266071, China
- School of Materials Science and Engineering, Shandong University of Technology, Zibo 255000, China
| | - Youqing Shen
- College of Chemistry and Chemical Engineering, College of Materials Science and Engineering, Institute of Biomedical Materials and Engineering, Qingdao University, Qingdao, 266071, China.
- Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Center for Bionanoengineering, and Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China
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23
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Chen L, Zhao D, Ren X, Ren J, Meng X, Fu C, Li X. Shikonin-Loaded Hollow Fe-MOF Nanoparticles for Enhanced Microwave Thermal Therapy. ACS Biomater Sci Eng 2023; 9:5405-5417. [PMID: 37638660 PMCID: PMC10498989 DOI: 10.1021/acsbiomaterials.3c00644] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/15/2023] [Indexed: 08/29/2023]
Abstract
Microwave (MW) thermal therapy has been widely used for the treatment of cancer in clinics, but it still shows limited efficacy and a high recurrence rate owing to non-selective heat delivery and thermo-resistance. Regulating glycolysis shows great promise to improve MW thermal therapy since glycolysis plays an important role in thermo-resistance, progression, metabolism, and recurrence. Herein, we developed a delivery nanosystem of shikonin (SK)-loaded and hyaluronic acid (HA)-modified hollow Fe-MOF (HFM), HFM@SK@HA, as an efficient glycolysis-meditated agent to improve the efficacy of MW thermal therapy. The HFM@SK@HA nanosystem shows a high SK loading capacity of 31.7 wt %. The loaded SK can be effectively released from the HFM@SK@HA under the stimulation of an acidic tumor microenvironment and MW irradiation, overcoming the intrinsically low solubility and severe toxicity of SK. We also find that the HFM@SK@HA can not only greatly improve the heating effect of MW in the tumor site but also mediate MW-enhancing dynamic therapy efficiency by catalyzing the endogenous H2O2 to generate reactive oxygen species (ROS). As such, the MW irradiation treatment in the presence of HFM@SK@HA in vitro enables a highly improved anti-tumor efficacy due to the combined effect of released SK and generated ROS on inhibiting glycolysis in cancer cells. Our in vivo experiments show that the tumor inhibition rate is up to 94.75% ± 3.63% with no obvious recurrence during the 2 weeks after treatment. This work provides a new strategy for improving the efficacy of MW thermal therapy.
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Affiliation(s)
- Lufeng Chen
- Department
of Radiation Oncology, First Clinical Medical
School and First Hospital of Shanxi Medical University, No.85 Jiefang Road, Taiyuan City 030001, PR China
| | - Dongming Zhao
- Department
of Radiation Oncology, First Clinical Medical
School and First Hospital of Shanxi Medical University, No.85 Jiefang Road, Taiyuan City 030001, PR China
- Department
of Pathology, Basic Medical School, Shanxi
Medical University, No.56 Xinjian Road, Taiyuan City 030001, PR China
| | - Xiangling Ren
- Laboratory
of Controllable Preparation and Application of Nanomaterials, Technical
Institute of Physics and Chemistry, Chinese
Academy of Sciences, No.29 East Road Zhongguancun, Beijing 100190, PR China
- CAS
Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Jun Ren
- Laboratory
of Controllable Preparation and Application of Nanomaterials, Technical
Institute of Physics and Chemistry, Chinese
Academy of Sciences, No.29 East Road Zhongguancun, Beijing 100190, PR China
- CAS
Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xianwei Meng
- Laboratory
of Controllable Preparation and Application of Nanomaterials, Technical
Institute of Physics and Chemistry, Chinese
Academy of Sciences, No.29 East Road Zhongguancun, Beijing 100190, PR China
- CAS
Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Changhui Fu
- Laboratory
of Controllable Preparation and Application of Nanomaterials, Technical
Institute of Physics and Chemistry, Chinese
Academy of Sciences, No.29 East Road Zhongguancun, Beijing 100190, PR China
- CAS
Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China
| | - Xianfeng Li
- Department
of Radiation Oncology, First Clinical Medical
School and First Hospital of Shanxi Medical University, No.85 Jiefang Road, Taiyuan City 030001, PR China
- Department
of Pathology, Basic Medical School, Shanxi
Medical University, No.56 Xinjian Road, Taiyuan City 030001, PR China
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24
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Qin Y, Zhang H, Li Y, Xie T, Yan S, Wang J, Qu J, Ouyang F, Lv S, Guo Z, Wei H, Yu CY. Promotion of ICD via Nanotechnology. Macromol Biosci 2023; 23:e2300093. [PMID: 37114599 DOI: 10.1002/mabi.202300093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/17/2023] [Indexed: 04/29/2023]
Abstract
Immunotherapy represents the most promising treatment strategy for cancer, but suffers from compromised therapeutic efficiency due to low immune activity of tumor cells and an immunosuppressive microenvironment, which significantly hampers the clinical translations of this treatment strategy. To promote immunotherapy with desired therapeutic efficiency, immunogenic cell death (ICD), a particular type of death capable of reshaping body's antitumor immune activity, has drawn considerable attention due to the potential to stimulate a potent immune response. Still, the potential of ICD effect remains unsatisfactory because of the intricate tumor microenvironment and multiple drawbacks of the used inducing agents. ICD has been thoroughly reviewed so far with a general classification of ICD as a kind of immunotherapy strategy and repeated discussion of the related mechanism. However, there are no published reviews, to the authors' knowledge, providing a systematic summarization on the enhancement of ICD via nanotechnology. For this purpose, this review first discusses the four stages of ICD according to the development mechanisms, followed by a comprehensive description on the use of nanotechnology to enhance ICD in the corresponding four stages. The challenges of ICD inducers and possible solutions are finally summarized for future ICD-based enhanced immunotherapy.
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Affiliation(s)
- Yang Qin
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Haitao Zhang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Yunxian Li
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Ting Xie
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Shuang Yan
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Jiaqi Wang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Jun Qu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Feijun Ouyang
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Shaoyang Lv
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Zifen Guo
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Hua Wei
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Cui-Yun Yu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy & Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, China
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25
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Moffett AS, Deng Y, Levine H. Modeling the Role of Immune Cell Conversion in the Tumor-Immune Microenvironment. Bull Math Biol 2023; 85:93. [PMID: 37658264 PMCID: PMC10474003 DOI: 10.1007/s11538-023-01201-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/17/2023] [Indexed: 09/03/2023]
Abstract
Tumors develop in a complex physical, biochemical, and cellular milieu, referred to as the tumor microenvironment. Of special interest is the set of immune cells that reciprocally interact with the tumor, the tumor-immune microenvironment (TIME). The diversity of cell types and cell-cell interactions in the TIME has led researchers to apply concepts from ecology to describe the dynamics. However, while tumor cells are known to induce immune cells to switch from anti-tumor to pro-tumor phenotypes, this type of ecological interaction has been largely overlooked. To address this gap in cancer modeling, we develop a minimal, ecological model of the TIME with immune cell conversion, to highlight this important interaction and explore its consequences. A key finding is that immune conversion increases the range of parameters supporting a co-existence phase in which the immune system and the tumor reach a stalemate. Our results suggest that further investigation of the consequences of immune cell conversion, using detailed, data-driven models, will be critical for greater understanding of TIME dynamics.
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Affiliation(s)
- Alexander S. Moffett
- Center for Theoretical Biological Physics, Northeastern University, Boston, MA 02115 USA
- Department of Physics, Northeastern University, Boston, MA 02115 USA
| | - Youyuan Deng
- Center for Theoretical Biological Physics, Rice University, Houston, TX 77005 USA
- Applied Physics Graduate Program, Smalley-Curl Institute, Rice University, Houston, TX 77005 USA
| | - Herbert Levine
- Center for Theoretical Biological Physics, Northeastern University, Boston, MA 02115 USA
- Department of Physics, Northeastern University, Boston, MA 02115 USA
- Department of Bioengineering, Northeastern University, Boston, MA 02115 USA
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26
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Zhang L, Cui S, Ding N, Zhang J, Cui E, Xiang Q, Zhou Z, Sun B, Wang Y, Hong H, Ma Y, Yang D. Tumor-Associated Macrophages Regulating a Polymer Nanoplatform for Synergistic Treatment of Breast Tumors. ACS APPLIED MATERIALS & INTERFACES 2023; 15:34527-34539. [PMID: 37462215 DOI: 10.1021/acsami.3c05497] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2023]
Abstract
Tumor-associated macrophages (TAMs) play a critical role in tumor progression and metastasis. Modulation of TAM polarization is one of the most effective strategies to change the immunosuppressive tumor microenvironment (TME). In this study, organic polymer nanoparticles (CPHT) were prepared using hyaluronic acid (HA)-conjugated disulfide-bonded polyethylene imide (PEIS) as a carrier through a self-assembly strategy. These nanoparticles were modified by transferrin (Tf) and loaded with chlorin e6 (Ce6). The results showed that CPHT had good dispersion with a particle size of about 30 nm. CPHT gradually disintegrated under the exposure with a high concentration of glutathione (GSH) in tumor cells, proving the possibility for the controlled release of Ce6 and photodynamic therapy. An in vitro test showed that the uptake of CPHT in tumor cells was mediated by both HA and Tf, indicating the active tumor-targeting capacity of CPHT. CPHT significantly downregulated the ratio of CD206/CD86 and triggered the upregulation of immune factors such as TNF-α and iNOS, suggesting the repolarization of TAMs. We also found that CPHT effectively induced ferroptosis in tumor cells through lipid peroxide accumulation, GSH depletion, and downregulation of lipid peroxidase (GPX4) expression. Animal experiments confirmed that CPHT not only effectively inhibited the growth of tumors in situ but also significantly decelerated the growth of the distal tumor. Elevated levels of CD86 and IFN-γ and decreased expression of CD206 were observed at the tumor sites post CPHT treatment. These results confirmed the value of CPHT as a multifunctional nanoplatform that can tune the TME and provide new hope for tumor treatment.
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Affiliation(s)
- Li Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Shuai Cui
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Ning Ding
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Jing Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Enna Cui
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Qian Xiang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Zhenghao Zhou
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Bo Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Yinan Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
| | - Hao Hong
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, PR China
| | - Yunsu Ma
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
- Jiangsu Yuanlong Hospital Management Co. LTD, Xuzhou, Jiangsu 221000, PR China
| | - Dongzhi Yang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, PR China
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27
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Tao H, Zhong X, Zeng A, Song L. Unveiling the veil of lactate in tumor-associated macrophages: a successful strategy for immunometabolic therapy. Front Immunol 2023; 14:1208870. [PMID: 37564659 PMCID: PMC10411982 DOI: 10.3389/fimmu.2023.1208870] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/12/2023] [Indexed: 08/12/2023] Open
Abstract
Lactate, traditionally regarded as a metabolic waste product at the terminal of the glycolysis process, has recently been found to have multifaceted functional roles in metabolism and beyond. A metabolic reprogramming phenomenon commonly seen in tumor cells, known as the "Warburg effect," sees high levels of aerobic glycolysis result in an excessive production of lactate. This lactate serves as a substrate that sustains not only the survival of cancer cells but also immune cells. However, it also inhibits the function of tumor-associated macrophages (TAMs), a group of innate immune cells ubiquitously present in solid tumors, thereby facilitating the immune evasion of malignant tumor cells. Characterized by their high plasticity, TAMs are generally divided into the pro-inflammatory M1 phenotype and the pro-tumour M2 phenotype. Through a process of 'education' by lactate, TAMs tend to adopt an immunosuppressive phenotype and collaborate with tumor cells to promote angiogenesis. Additionally, there is growing evidence linking metabolic reprogramming with epigenetic modifications, suggesting the participation of histone modification in diverse cellular events within the tumor microenvironment (TME). In this review, we delve into recent discoveries concerning lactate metabolism in tumors, with a particular focus on the impact of lactate on the function of TAMs. We aim to consolidate the molecular mechanisms underlying lactate-induced TAM polarization and angiogenesis and explore the lactate-mediated crosstalk between TAMs and tumor cells. Finally, we also touch upon the latest progress in immunometabolic therapies and drug delivery strategies targeting glycolysis and lactate production, offering new perspectives for future therapeutic approaches.
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Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xuansheng Zhong
- Clinical Medicine Department, Bengbu Medical College, Bengbu, China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan, China
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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28
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Long L, Xiong W, Lin F, Hou J, Chen G, Peng T, He Y, Wang R, Xu Q, Huang Y. Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery. J Exp Clin Cancer Res 2023; 42:117. [PMID: 37161591 PMCID: PMC10170793 DOI: 10.1186/s13046-023-02688-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/26/2023] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. METHODS A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. RESULTS SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFβ signaling; the amount of cytotoxic effector CD8+ T cells was increased while the immunosuppressive MDSCs decreased. CONCLUSION The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT.
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Affiliation(s)
- Li Long
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wei Xiong
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Fenwang Lin
- Department of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jiazhen Hou
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Guihua Chen
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Taoxing Peng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Yihao He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Rui Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Qin Xu
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China.
| | - Yongzhuo Huang
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China.
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China.
- NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai, 201203, China.
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29
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Zou L, Liu K, Shi Y, Li G, Li H, Zhao C. ScRNA-seq revealed targeting regulator of G protein signaling 1 to mediate regulatory T cells in Hepatocellular carcinoma. Cancer Biomark 2023; 36:299-311. [PMID: 36938729 DOI: 10.3233/cbm-220226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
BACKGROUND Regulatory T cells (Tregs) are central to determine immune response outcomes, thus targeting Tregs for immunotherapy is a promising strategy against tumor development and metastasis. OBJECTIVES The objective of this study was to identify genes for targeting Tregs to improve the outcome of HCC. METHODS We integrated expression data from different samples to remove batch effects and further applied embedding function in Scanpy to conduct sub-clustering of CD4+ T cells in HCC for each of two independent scRNA-seq data. The activity of transcription factors (TFs) was inferred by DoRothEA. Gene expression network analysis was performed in WGCNA R package. We finally used R packages (survminer and survival) to conduct survival analysis. Multiplex immunofluorescence analysis was performed to validate the result from bioinformatic analyses. RESULTS We found that regulator of G protein signaling 1 (RGS1) expression was significantly elevated in Tregs compared to other CD4+ T cells in two independent public scRNA-seq datasets, and increased RGS1 predicted inferior clinical outcome of HCC patients. Multiplex immunofluorescence analysis supported that the higher expression of RGS1 in HCC Tregs in tumor tissue compared to it in adjacent tissue. Moreover, RGS1 expression in Tregs was positively correlated with the expression of marker genes of Tregs, C-X-C chemokine receptor 4 (CXCR4), and three CXCR4-dependent genes in both scRNA-seq and bulk RNA-seq data. We further identified that these three genes were selectively expressed in Tregs as compared to other CD4+ T cells. The activities of two transcription factors, recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and yin yang 1 (YY1), were significantly different in HCC Tregs with RGS1 high and RGS1 low. CONCLUSIONS Our findings suggested that RGS1 may regulate Treg function possibly through CXCR4 signaling and RGS1 could be a potential target to improve responses for immunotherapy in HCC.
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Affiliation(s)
- Lianhong Zou
- Institute of Translational Medicine, Hunan Provincial People's Hospital, First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Kaihua Liu
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Yongzhong Shi
- Institute of Translational Medicine, Hunan Provincial People's Hospital, First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Guowei Li
- Department of Hepatobiliary Surgery, The First People'S Hospital of Guiyang, Guiyang, Guizhou, China
| | - Haiyang Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Chaoxian Zhao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
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30
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Li M, Yang J, Yao X, Li X, Xu Z, Tang S, Sun B, Lin S, Yang C, Liu J. Multifunctional Mesoporous Silica-Coated Gold Nanorods Mediate Mild Photothermal Heating-Enhanced Gene/Immunotherapy for Colorectal Cancer. Pharmaceutics 2023; 15:pharmaceutics15030854. [PMID: 36986715 PMCID: PMC10057058 DOI: 10.3390/pharmaceutics15030854] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths in the world. It is urgent to search for safe and effective therapies to address the CRC crisis. The siRNA-based RNA interference targeted silencing of PD-L1 has extensive potential in CRC treatment but is limited by the lack of efficient delivery vectors. In this work, the novel cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs)/siPD-L1 co-delivery vectors AuNRs@MS/CpG ODN@PEG-bPEI (ASCP) were successfully prepared by two-step surface modification of CpG ODNs-loading and polyethylene glycol-branched polyethyleneimine-coating around mesoporous silica-coated gold nanorods. ASCP promoted dendritic cells (DCs) maturation by delivering CpG ODNs, exhibiting excellent biosafety. Next, mild photothermal therapy (MPTT) mediated by ASCP killed tumor cells and released tumor-associated antigens, further promoting DC maturation. Furthermore, ASCP exhibited mild photothermal heating-enhanced performance as gene vectors, resulting in an increased PD-L1 gene silencing effect. Enhanced DCs maturity and enhanced PD-L1 gene silencing significantly promoted the anti-tumor immune response. Finally, the combination of MPTT and mild photothermal heating-enhanced gene/immunotherapy effectively killed MC38 cells, leading to strong inhibition of CRC. Overall, this work provided new insights into the design of mild photothermal/gene/immune synergies for tumor therapy and may contribute to translational nanomedicine for CRC treatment.
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Affiliation(s)
- Meirong Li
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
- Central Laboratory of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen 518172, China
| | - Jingyu Yang
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Xinhuang Yao
- Central Laboratory of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen 518172, China
| | - Xiang Li
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Zhourui Xu
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Shiqi Tang
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
| | - Bangxu Sun
- Central Laboratory of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen 518172, China
| | - Suxia Lin
- Center of Assisted Reproduction and Embryology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518048, China
| | - Chengbin Yang
- School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University, Shenzhen 518060, China
- Correspondence: (C.Y.); (J.L.)
| | - Jia Liu
- Central Laboratory of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Shenzhen 518172, China
- Correspondence: (C.Y.); (J.L.)
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Li S, Dong S, Wu J, Lv X, Yang N, Wei Q, Wang C, Chen J. Surgically Derived Cancer Cell Membrane-Coated R837-Loaded Poly(2-Oxazoline) Nanoparticles for Prostate Cancer Immunotherapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:7878-7886. [PMID: 36738473 PMCID: PMC9940722 DOI: 10.1021/acsami.2c22363] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/23/2023] [Indexed: 06/18/2023]
Abstract
Cancer cell membranes (CCMs) are widely used as sources of tumor-associated antigens (TAAs) for the development of cancer vaccines. To improve the CCM-associated cancer vaccine efficiency, personalized cancer vaccines and effective delivery systems are required. In this study, we employed surgically harvested cancer tissues to prepare personalized CCMs for use as TAAs. Thioglycolic-acid-grafted poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline-co-2-butenyl-2-oxazoline) (PMBEOx-COOH) was synthesized to load imiquimod (R837) efficiently. The personalized CCMs were then coated onto R837-loaded PMBEOx-COOH nanoparticles (POxTA NPs/R837) to obtain surgically derived CCM-coated POxTA NPs (SCNPs/R837). SCNPs/R837 efficiently travelled to the draining lymph nodes and were taken up and presented by plasmacytoid dendritic cells to elicit enhanced antitumor immune responses. When combined with programmed cell death-1 antibodies, SCNPs/R837 exhibited high efficiency corresponding to antitumor progression. Therefore, SCNP/R837 might represent a promising personalized cancer vaccine with significant potential for cancer immunotherapy.
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Affiliation(s)
- Shengxian Li
- Department
of Urology, The First Hospital of Jilin
University, Changchun130021, P. R. China
- Department
of Urology, The Affiliated Hospital of Qingdao
University, Qingdao266003, P.R. China
| | - Si Dong
- College
of Chemistry, Northeast Normal University, Changchun130024, P.R. China
| | - Jing Wu
- Laboratory
for Tumor Immunology, The First Hospital
of Jilin University, Changchun130061, P.R. China
| | - Xinping Lv
- Laboratory
for Tumor Immunology, The First Hospital
of Jilin University, Changchun130061, P.R. China
| | - Ning Yang
- Laboratory
for Tumor Immunology, The First Hospital
of Jilin University, Changchun130061, P.R. China
| | - Qiuyu Wei
- Laboratory
for Tumor Immunology, The First Hospital
of Jilin University, Changchun130061, P.R. China
| | - Chunxi Wang
- Department
of Urology, The First Hospital of Jilin
University, Changchun130021, P. R. China
| | - Jingtao Chen
- Laboratory
for Tumor Immunology, The First Hospital
of Jilin University, Changchun130061, P.R. China
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32
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KNSTRN, a Poor Prognostic Biomarker, Affects the Tumor Immune Microenvironment and Immunotherapy Outcomes in Pan-Cancer. DISEASE MARKERS 2023; 2023:6729717. [PMID: 36845017 PMCID: PMC9946745 DOI: 10.1155/2023/6729717] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/07/2023] [Accepted: 01/12/2023] [Indexed: 02/17/2023]
Abstract
Kinetochore-localized astrin- (SPAG5-) binding protein (KNSTRN) is mainly involved in mitosis. Somatic mutations in KNSTRN are known to lead to the occurrence and development of certain tumors. However, the role of KNSTRN in the tumor immune microenvironment (TIME) as a tumor prognostic biomarker and potential therapeutic target has not been clarified. Accordingly, in this study, we aimed to investigate the role of KNSTRN in the TIME. mRNA expression, cancer patient prognosis, and correlations between KNSTRN expression and immune component infiltration were analyzed using Genotype-Tissue Expression, The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Human Protein Atlas, ImmuCellAI, TIMER2.0, and KM-Plotter. The Genomics of Drug Sensitivity in Cancer database was used to evaluate the relationship between KNSTRN expression and the half maximal inhibitory concentration (IC50) of several anticancer drugs, and gene set variation analysis was performed. Data were visualized using R version 4.1.1. KNSTRN expression was upregulated in the majority of cancers and was associated with a worse prognosis. Additionally, KNSTRN expression was highly correlated with the infiltration of multiple immune components in the TIME and was related to a poor prognosis in tumor patients receiving immunotherapy. KNSTRN expression was also positively correlated with the IC50 of various anticancer drugs. In conclusion, KNSTRN may be a significant prognostic biomarker and promising target for oncotherapy in numerous cancers.
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33
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Zhang J, Zou S, Fang L. Metabolic reprogramming in colorectal cancer: regulatory networks and therapy. Cell Biosci 2023; 13:25. [PMID: 36755301 PMCID: PMC9906896 DOI: 10.1186/s13578-023-00977-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.
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Affiliation(s)
- Jieping Zhang
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Shaomin Zou
- grid.12981.330000 0001 2360 039XDepartment of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655 Guangdong China ,Guangdong Institute of Gastroenterology, Guangzhou, 510655 China
| | - Lekun Fang
- Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-Sen University, 26 Yuanchun Er Heng Road, Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangzhou, 510655, China.
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34
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Chen J, Zhu Y, Wu C, Shi J. Engineering lactate-modulating nanomedicines for cancer therapy. Chem Soc Rev 2023; 52:973-1000. [PMID: 36597879 DOI: 10.1039/d2cs00479h] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Lactate in tumors has long been considered "metabolic junk" derived from the glycolysis of cancer cells and utilized only as a biomarker of malignancy, but is presently believed to be a pivotal regulator of tumor development, maintenance and metastasis. Indeed, tumor lactate can be a "fuel" for energy supply and functions as a signaling molecule, which actively contributes to tumor progression, angiogenesis, immunosuppression, therapeutic resistance, etc., thus providing promising opportunities for cancer treatment. However, the current approaches for regulating lactate homeostasis with available agents are still challenging, which is mainly due to the short half-life, low bioavailability and poor specificity of these agents and their unsatisfactory therapeutic outcomes. In recent years, lactate modulation nanomedicines have emerged as a charming and efficient strategy for fighting cancer, which play important roles in optimizing the delivery of lactate-modulating agents for more precise and effective modulation and treatment. Integrating specific lactate-modulating functions in diverse therapeutic nanomedicines may overcome the intrinsic restrictions of different therapeutic modalities by remodeling the pathological microenvironment for achieving enhanced cancer therapy. In this review, the most recent advances in the engineering of functional nanomedicines that can modulate tumor lactate for cancer therapy are summarized and discussed, and the fundamental mechanisms by which lactate modulation benefits various therapeutics are elucidated. Finally, the challenges and perspectives of this emerging strategy in the anti-tumor field are highlighted.
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Affiliation(s)
- Jiajie Chen
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yufang Zhu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Chengtie Wu
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Jianlin Shi
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, P. R. China. .,Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.,Shanghai Tenth People's Hospital, Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, 200331, P. R. China
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35
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Chen Y, Xiong T, Zhao X, Du J, Sun W, Fan J, Peng X. Tumor Cell-Responsive Photodynamic Immunoagent for Immunogenicity-Enhanced Orthotopic and Remote Tumor Therapy. Adv Healthc Mater 2023; 12:e2202085. [PMID: 36377488 DOI: 10.1002/adhm.202202085] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/08/2022] [Indexed: 11/16/2022]
Abstract
Combining photodynamic therapy (PDT) and immune checkpoint blockades is an efficient method to maximize immunotherapeutic outcome by boosting tumor immunogenicity and modulating the immunosuppressive tumor microenvironment. However, the always-on bioactivity of photosensitizers or immune checkpoint inhibitors leads to uncontrollable side effects, limiting the in vivo therapeutic efficacy of treatments. An activatable strategy is of great importance for improving the selectivity during cancer therapy. In this study, a photodynamic immunomodulator, ICy-NLG, is developed by conjugating the photosensitizer ICy-NH2 with the indoleamine 2,3-dioxygenase 1 inhibitor NLG919 through a glutathione (GSH)-cleavable linker to achieve activatable photodynamic immunotherapy. The conjugation considerably suppresses both the PDT effect and the activity of the inhibitor. After ICy-NLG is activated by high levels of GSH in tumor cells, the PDT effect is restored and leads to immunogenic tumor cell death. The released tumor-associated antigens in conjunction with the activated immune checkpoint inhibitor induce a synergistic antitumor immune response, resulting in the growth inhibition of primary and distant tumors and the prevention of lung metastasis in mouse xenograft models.
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Affiliation(s)
- Yingchao Chen
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
| | - Tao Xiong
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
| | - Xueze Zhao
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
| | - Jianjun Du
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
| | - Wen Sun
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China
| | - Jiangli Fan
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China.,Research Institute of Dalian University of Technology in Shenzhen, Gaoxin South Fourth Road, Nanshan District, Shenzhen, 518057, China
| | - Xiaojun Peng
- State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian, 116024, China.,Research Institute of Dalian University of Technology in Shenzhen, Gaoxin South Fourth Road, Nanshan District, Shenzhen, 518057, China
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36
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Yang H, Hu Y, Kong D, Chen P, Yang L. Intralesional Bacillus Calmette-Guérin injections and hypo-fractionated radiation synergistically induce systemic antitumor immune responses. Int Immunopharmacol 2023; 114:109542. [PMID: 36521291 DOI: 10.1016/j.intimp.2022.109542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 12/01/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022]
Abstract
Radiotherapy, an important treatment for multiple malignancies, produces systemic anti-tumor effects in combination with immunotherapies, especially immune checkpoint inhibitors (ICBs). However, for some patients who do not respond to ICB treatment or show ICB-induced autoimmune symptoms, new alternatives need to be explored. Innovative immunomodulatory strategies, including the administration of immunostimulants, could be used to improve the immunogenicity induced by radiotherapy. In this study, we explored the synergistic effect of Bacillus Calmette-Guérin (BCG) combined with hypo-fractionated radiotherapy (H-RT) in inducing anti-tumor immune responses. We observed the systemic and abscopal effects of this combination in mice with 4 T1 breast cancer. H-RT combined with BCG could remodel the immune microenvironment and alleviate leukocyte-like responses by increasing the infiltration of CD8 + T cells, promoting the maturation of dendritic cells (DCs), decreasing the infiltration of immunosuppressive cells, and downregulating the expression of immunosuppressive cytokines. Therefore, this combination could enhance the systemic anti-tumor response, leading to the regression of untreated synchronous tumors and a decrease in the systemic metastatic burden. These results highlight the potential of BCG in assisting antitumor therapy and the therapeutic potential of this combination treatment.
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Affiliation(s)
- Hanshan Yang
- Medical Center of Hematology, the Second Affiliated Hospital, Army Medical University, Chongqing 400000, China; Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yuru Hu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Deyi Kong
- Department of Encephalopathy, Jiang 'an Hospital of Traditional Chinese Medicine, Yibin 644000, China
| | - Ping Chen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Linglin Yang
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
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37
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Yan C, Li Q, Sun Q, Yang L, Liu X, Zhao Y, Shi M, Li X, Luo K. Promising Nanomedicines of Shikonin for Cancer Therapy. Int J Nanomedicine 2023; 18:1195-1218. [PMID: 36926681 PMCID: PMC10013574 DOI: 10.2147/ijn.s401570] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/15/2023] [Indexed: 03/18/2023] Open
Abstract
Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.
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Affiliation(s)
- Chunmei Yan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Qiuxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Qiang Sun
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Lu Yang
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Yuxin Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Mingyi Shi
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
| | - Kaipei Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
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38
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Ding YN, Xue M, Tang QS, Wang LJ, Ding HY, Li H, Gao CC, Yu WP. Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges. World J Gastroenterol 2022; 28:5403-5419. [PMID: 36312831 PMCID: PMC9611702 DOI: 10.3748/wjg.v28.i37.5403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/27/2022] [Accepted: 09/15/2022] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.
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Affiliation(s)
- Yi-Nan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Ming Xue
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Qiu-Sha Tang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Li-Jun Wang
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Hui-Yan Ding
- Department of Pathophysiology, College of Medicine, Southeast University, Nanjing 210000, Jiangsu Province, China
| | - Han Li
- Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Cheng-Cheng Gao
- Department of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Ping Yu
- Medical School, Southeast University, Nanjing 210009, Jiangsu Province, China
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Chen S, Wang J, Tang K, Liao H, Xu Y, Wang L, Niu C. Multi-Modal Imaging Monitored M2 Macrophage Targeting Sono-Responsive Nanoparticles to Combat MRSA Deep Infections. Int J Nanomedicine 2022; 17:4525-4546. [PMID: 36193213 PMCID: PMC9526443 DOI: 10.2147/ijn.s383237] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/13/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND MRSA with high morbidity and mortality is prone to cause serious infection, SDT has become a new antibiotic-free modality for bacterial infection treatment. Switching from proinflammatory M1 macrophages to anti-inflammatory M2 macrophages dominant could activate the immune system to generate an anti-infection immune response. METHODS Herein, we developed M2 macrophages derived cell membranes coated PLGA nanoparticles with IR780 encapsulation (M2/IR780@PLGA) for antibacterial SDT and subsequent M2 macrophage polarization to enhance the therapeutic efficacy of MRSA myositis. For in situ visualization of antibacterial SDT, both diagnostic high-frequency US and magnetic resonance imaging (MRI) were introduced to monitor the sono-therapeutic progression of M2/IR780@PLGA nanoparticles in mice with bacterial myositis. RESULTS Our developed M2/IR780@PLGA nanoparticles exhibited excellent antibacterial effects due to the IR780 under low-frequency US irradiation in vitro. In an MRSA-infected mice model, a great deal of M2/IR780@PLGA nanoparticles accumulated at the site of inflammation due to M2 macrophage coating. The infected legs in the M2/IR780@PLGA nanoparticles-based SDT group were significantly smaller, fewer blood flow signals, a slight muscular edema without obvious intermuscular abscesses under high-frequency US and MR images guidance. Histopathology proved the infected legs in the M2/IR780@PLGA nanoparticles-mediated SDT group had less clumped bacteria infiltration, more M2 macrophage expression and less M1 macrophage expression. The percentage of mature dendritic cells in spleens was much higher in the group of mice with M2/IR780@PLGA nanoparticles-based SDT. CONCLUSION This study provides a promising nanoparticles-based SDT anti-bacterial strategy, which could effectively enhance the antibacterial SDT and subsequent promote M2 macrophage polarization to boost the therapeutic efficacy of MRSA myositis.
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Affiliation(s)
- Sijie Chen
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Jiahao Wang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Kui Tang
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Haiqin Liao
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Yan Xu
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Long Wang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
| | - Chengcheng Niu
- Department of Ultrasound Diagnosis, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
- Research Center of Ultrasonography, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China
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Wu JY, Song QY, Huang CZ, Shao Y, Wang ZL, Zhang HQ, Fu Z. N7-methylguanosine-related lncRNAs: Predicting the prognosis and diagnosis of colorectal cancer in the cold and hot tumors. Front Genet 2022; 13:952836. [PMID: 35937987 PMCID: PMC9352958 DOI: 10.3389/fgene.2022.952836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: 7-Methylguanosine(m7G) contributes greatly to its pathogenesis and progression in colorectal cancer. We proposed building a prognostic model of m7G-related LncRNAs. Our prognostic model was used to identify differences between hot and cold tumors.Methods: The study included 647 colorectal cancer patients (51 cancer-free patients and 647 cancer patients) from The Cancer Genome Atlas (TCGA). We identified m7G-related prognostic lncRNAs by employing the univariate Cox regression method. Assessments were conducted using univariate Cox regression, multivariate Cox regression, receiver operating characteristics (ROC), nomogram, calibration curves, and Kaplan-Meier analysis. All of these procedures were used with the aim of confirming the validity and stability of the model. Besides these two analyses, we also conducted half-maximal inhibitory concentration (IC50), immune analysis, principal component analysis (PCA), and gene set enrichment analysis (GSEA). The entire set of m7G-related (lncRNAs) with respect to cold and hot tumors has been divided into two clusters for further discussion of immunotherapy.Results: The risk model was constructed with 17 m7G-related lncRNAs. A good correlation was found between the calibration plots and the prognosis prediction in the model. By assessing IC50 in a significant way across risk groups, systemic treatment can be guided. By using clusters, it may be possible to distinguish hot and cold tumors effectively and to aid in specific therapeutic interventions. Cluster 1 was identified as having the highest response to immunotherapy drugs and thus was identified as the hot tumor.Conclusion: This study shows that 17 m7G-related lncRNA can be used in clinical settings to predict prognosis and use them to determine whether a tumor is cold or hot in colorectal cancer and improve the individualization of treatment.
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Affiliation(s)
- Jing-Yu Wu
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing-Yu Song
- The General Surgery Laboratory, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chang-Zhi Huang
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yu Shao
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhen-Ling Wang
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hong-Qiang Zhang
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zan Fu
- The General Surgery Laboratory, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Zan Fu,
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Yadav S, Sharma A, Nayik GA, Cooper R, Bhardwaj G, Sohal HS, Mutreja V, Kaur R, Areche FO, AlOudat M, Shaikh AM, Kovács B, Mohamed Ahmed AE. Review of Shikonin and Derivatives: Isolation, Chemistry, Biosynthesis, Pharmacology and Toxicology. Front Pharmacol 2022; 13:905755. [PMID: 35847041 PMCID: PMC9283906 DOI: 10.3389/fphar.2022.905755] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Accepted: 05/30/2022] [Indexed: 12/19/2022] Open
Abstract
Shikonin and its derivatives, isolated from traditional medicinal plant species of the genus Lithospermum, Alkanna, Arnebia, Anchusa, Onosma, and Echium belonging to the Boraginaceae family, have numerous applications in foods, cosmetics, and textiles. Shikonin, a potent bioactive red pigment, has been used in traditional medicinal systems to cure various ailments and is well known for its diverse pharmacological potential such as anticancer, antithrombotic, neuroprotective, antidiabetic, antiviral, anti-inflammatory, anti-gonadotropic, antioxidants, antimicrobial and insecticidal. Herein, updated research on the natural sources, pharmacology, toxicity studies, and various patents filed worldwide related to shikonin and approaches to shikonin’s biogenic and chemical synthesis are reviewed. Furthermore, recent studies to establish reliable production systems to meet market demand, functional identification, and future clinical development of shikonin and its derivatives against various diseases are presented.
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Affiliation(s)
- Snehlata Yadav
- Department of Chemistry, Chandigarh University, Mohali, India
| | - Ajay Sharma
- Department of Chemistry, Chandigarh University, Mohali, India
- University Centre for Research and Development, Department of Chemistry, Chandigarh University, Chandigarh- Ludhiana Highway, Mohali, India
| | - Gulzar Ahmad Nayik
- Department of Food Science & Technology, Govt. Degree College Shopian, Srinagar, India
| | - Raymond Cooper
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Garima Bhardwaj
- Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal, Sangrur, India
| | | | - Vishal Mutreja
- Department of Chemistry, Chandigarh University, Mohali, India
| | - Ramandeep Kaur
- Department of Chemistry, Punjab Agricultural University, Ludhiana, India
| | - Franklin Ore Areche
- Professional School of Agroindustrial Engineering, National University of Huancavelica, Huancavelica, Peru
| | - Mohannad AlOudat
- Doctoral School of Food Science, Hungarian University of Agriculture and Life Sciences, Budapset, Hungary
| | | | - Béla Kovács
- Institute of Food Science, University of Debrecen, Debrecen, Hungary
| | - Abdelhakam Esmaeil Mohamed Ahmed
- Institute of Food Science, University of Debrecen, Debrecen, Hungary
- Faculty of Forestry, University of Khartoum, Khartoum North, Sudan
- *Correspondence: Abdelhakam Esmaeil Mohamed Ahmed,
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Ling J, Chang Y, Yuan Z, Chen Q, He L, Chen T. Designing Lactate Dehydrogenase-Mimicking SnSe Nanosheets To Reprogram Tumor-Associated Macrophages for Potentiation of Photothermal Immunotherapy. ACS APPLIED MATERIALS & INTERFACES 2022; 14:27651-27665. [PMID: 35675569 DOI: 10.1021/acsami.2c05533] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.
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Affiliation(s)
- Jiabao Ling
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Yanzhou Chang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Zhongwen Yuan
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Qi Chen
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Lizhen He
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
| | - Tianfeng Chen
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Department of Chemistry, Jinan University, Guangzhou 510632, China
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Macrophage-targeted shikonin-loaded nanogels for modulation of inflammasome activation. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 42:102548. [PMID: 35301158 DOI: 10.1016/j.nano.2022.102548] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 02/23/2022] [Accepted: 03/06/2022] [Indexed: 10/18/2022]
Abstract
This study reports the formulation and delivery of hyaluronic acid-Zein (HA-Zein) nanogels loaded with Shikonin (SK) to selectively attenuate macrophage inflammasome. The self-assembled nanogels, produced by nanoprecipitation, exhibited high encapsulation efficiency, and were selectively internalized by human THP-1-derived macrophages without eliciting cytotoxic responses. Cell treatment with HA-Zein-SK nanogels before stimulation with LPS and Nigericin significantly suppressed caspase-1 activation and IL-1β production, indicating inflammasome inhibition. Importantly, HA-Zein-SK nanogels bioinstructed inflammasome activated macrophages towards an anti-inflammatory CD163highHLA-DRlow phenotype and led to a marked reduction in the release of pro-inflammatory mediators (TNF-α, IL-6 and IP-10). Extracellular metabolic profiling additionally revealed SK-mediated downregulation of cellular glycolytic activity, which was corroborated by a significant decrease of glycolytic genes transcription. All in all, our findings demonstrate the potential of bioactive SK-containing, self-assembled nanogels to modulate exacerbated responses in innate immune cells and, prospectively, in human tissues where NRLP3 inflammasome is abnormally activated upon injury or disease.
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Pu Y, Ji Q. Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression. Front Immunol 2022; 13:874589. [PMID: 35592338 PMCID: PMC9110638 DOI: 10.3389/fimmu.2022.874589] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/06/2022] [Indexed: 12/17/2022] Open
Abstract
Anti-programmed cell death 1 (PD-1) or anti-PD-ligand (L) 1 drugs, as classic immune checkpoint inhibitors, are considered promising treatment strategies for tumors. In clinical practice, some cancer patients experience drug resistance and disease progression in the process of anti-PD-1/PD-L1 immunotherapy. Tumor-associated macrophages (TAMs) play key roles in regulating PD-1/PD-L1 immunosuppression by inhibiting the recruitment and function of T cells through cytokines, superficial immune checkpoint ligands, and exosomes. There are several therapies available to recover the anticancer efficacy of PD-1/PD-L1 inhibitors by targeting TAMs, including the inhibition of TAM differentiation and re-education of TAM activation. In this review, we will summarize the roles and mechanisms of TAMs in PD-1/PD-L1 blocker resistance. Furthermore, we will discuss the therapies that were designed to deplete TAMs, re-educate TAMs, and intervene with chemokines secreted by TAMs and exosomes from M1 macrophages, providing more potential options to improve the efficacy of PD-1/PD-L1 inhibitors.
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Affiliation(s)
- Yunzhou Pu
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Design of Smart Nanomedicines for Effective Cancer Treatment. Int J Pharm 2022; 621:121791. [PMID: 35525473 DOI: 10.1016/j.ijpharm.2022.121791] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/22/2022]
Abstract
Nanomedicine is a novel field of study that involves the use of nanomaterials to address challenges and issues that are associated with conventional therapeutics for cancer treatment including, but not limited to, low bioavailability, low water-solubility, narrow therapeutic window, nonspecific distribution, and multiple side effects of the drugs. Multiple strategies have been exploited to reduce the nonspecific distribution, and thus the side effect of the active pharmaceutical ingredients (API), including active and passive targeting strategies and externally controllable release of the therapeutic cargo. Site-specific release of the drug prevents it from impacting healthy cells, thereby significantly reducing side effects. API release triggers can be either externally applied, as in ultrasound-mediated activation, or induced by the tumor. To rationally design such nanomedicines, a thorough understanding of the differences between the tumor microenvironment versus that of healthy tissues must be pared with extensive knowledge of stimuli-responsive biomaterials. Herein, we describe the characteristics that differentiate tumor tissues from normal tissues. Then, we introduce smart materials that are commonly used for the development of smart nanomedicines to be triggered by stimuli such as changes in pH, temperature, and enzymatic activity. The most recent advances and their impact on the field of cancer therapy are further discussed.
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Ma J, Zhang C, Shi G, Yue D, Shu Y, Hu S, Qi Z, Chen Y, Zhang B, Zhang Y, Huang A, Su C, Zhang Y, Deng H, Cheng P. High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment. Mol Ther 2022; 30:644-661. [PMID: 34547462 PMCID: PMC8821933 DOI: 10.1016/j.ymthe.2021.09.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 08/25/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023] Open
Abstract
Preclinical and clinical studies have validated the antitumor effects of several oncolytic viruses (OVs). However, the efficacy of OVs is limited when they are administered as monotherapies. Combination therapy is a promising direction for oncolytic virotherapy in the future. A high dose of vitamin C (VitC) exerts anticancer effects by triggering the accretion of substantial amounts of reactive oxygen species (ROS). OVs can induce immunogenic tumor cell death and elicit an antitumor immune response. ROS play an important role in immunogenic cell death (ICD). This study aimed to explore whether high-dose VitC in combination with oncolytic adenoviruses (oAds) exhibited a synergistic antitumor effect. High-dose VitC synergized with oAds against tumor by enhancing immunogenic tumor cell death. Combination therapy with high-dose VitC and oAds significantly increased the number of T cells in the tumor microenvironment (TME) and promoted the activation of T cells. Furthermore, the antitumor effect of the combination therapy was CD8+ T cell dependent. In addition, combination therapy with high-dose VitC and oAds reprogramed the immunosuppressive TME. Our study provides a new strategy for combination therapy of OVs.
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Affiliation(s)
- Jinhu Ma
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Chunxue Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Dan Yue
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, PR China
| | - Yongheng Shu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Shichuan Hu
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Zhongbing Qi
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Yanwei Chen
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Bin Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Yong Zhang
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Anliang Huang
- Department of Pathology, Chengdu Fifth People’s Hospital, Chengdu, PR China
| | - Chao Su
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Yan Zhang
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China,Corresponding author: Prof. Ping Cheng, State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17 People’s South Road, Chengdu 610041, PR China.
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Zhang J, Lin Y, Lin Z, Wei Q, Qian J, Ruan R, Jiang X, Hou L, Song J, Ding J, Yang H. Stimuli-Responsive Nanoparticles for Controlled Drug Delivery in Synergistic Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103444. [PMID: 34927373 PMCID: PMC8844476 DOI: 10.1002/advs.202103444] [Citation(s) in RCA: 117] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/28/2021] [Indexed: 05/10/2023]
Abstract
Cancer immunotherapy has achieved promising clinical progress over the recent years for its potential to treat metastatic tumors and inhibit their recurrences effectively. However, low patient response rates and dose-limiting toxicity remain as major dilemmas for immunotherapy. Stimuli-responsive nanoparticles (srNPs) combined with immunotherapy offer the possibility to amplify anti-tumor immune responses, where the weak acidity, high concentration of glutathione, overexpressions of enzymes, and reactive oxygen species, and external stimuli in tumors act as triggers for controlled drug release. This review highlights the design of srNPs based on tumor microenvironment and/or external stimuli to combine with different anti-tumor drugs, especially the immunoregulatory agents, which eventually realize synergistic immunotherapy of malignant primary or metastatic tumors and acquire a long-term immune memory to prevent tumor recurrence. The authors hope that this review can provide theoretical guidance for the construction and clinical transformation of smart srNPs for controlled drug delivery in synergistic cancer immunotherapy.
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Affiliation(s)
- Jin Zhang
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Yandai Lin
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Zhe Lin
- Ruisi (Fujian) Biomedical Engineering Research Center Co LtdFuzhou350100P. R. China
| | - Qi Wei
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
- State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200433P. R. China
| | - Jiaqi Qian
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Renjie Ruan
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Xiancai Jiang
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Linxi Hou
- Qingyuan Innovation LaboratoryCollege of Chemical EngineeringFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Jibin Song
- MOE Key Laboratory for Analytical Science of Food Safety and BiologyState Key Laboratory of Photocatalysis on Energy and EnvironmentCollege of ChemistryFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
| | - Jianxun Ding
- Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun130022P. R. China
- State Key Laboratory of Molecular Engineering of PolymersFudan University220 Handan RoadShanghai200433P. R. China
| | - Huanghao Yang
- MOE Key Laboratory for Analytical Science of Food Safety and BiologyState Key Laboratory of Photocatalysis on Energy and EnvironmentCollege of ChemistryFuzhou University2 Xueyuan RoadFuzhou350108P. R. China
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Codelivery of Shikonin and siTGF-β for enhanced triple negative breast cancer chemo-immunotherapy. J Control Release 2022; 342:308-320. [PMID: 35031387 DOI: 10.1016/j.jconrel.2022.01.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 11/25/2021] [Accepted: 01/08/2022] [Indexed: 02/08/2023]
Abstract
Although chemoimmunotherapy has achieved considerable success in cancer treatment in recent years, the cure for triple-negative breast cancer (TNBC) remains elusive. The unsatisfied outcomes are likely attributed to deficient tumor immunogenicity, a strong immunosuppressive tumor microenvironment (ITM) and tumor metastasis. To address this issue, we constructed an effective codelivery system, combined with tumor growth factor β (TGF-β) small interference RNA (siTGF-β) and shikonin (SK), to achieve successful chemoimmunotherapy of TNBC. The SK/siTGF-β NPs (approximately 110 nm) exhibited a uniform structure and good stability. Conjugated FA presented enhanced cellular uptake in 4 T1 cells, and siTGF-β escaped from lysosomes because of the "proton sponge" effect of PEI. Furthermore, SK actually induced satisfactory immunogenic cell death (ICD) and the resulting dendritic cell (DC) maturation facilitated a distinctly enhanced cytotoxic T lymphocyte (CTL) response, generating a positive effect on tumor suppression. Simultaneously, the successful silencing of TGF-β alleviated the TGF-β-mediated ITM and inhibited the epithelial-to-mesenchymal transition (EMT), contributing to the infiltration of CTLs, suppression of regulatory T lymphocyte (Treg) proliferation and lung metastasis inhibition. Thus, the SK/siTGF-β NPs demonstrated the strongest therapeutic effect with delayed tumor growth (TIR = 88.5%) and lung metastasis restraint (77.3%). More importantly, tumor rechallenge assay suggested that the codelivery system produced a long-term immunological memory response to prevent tumor recurrence. Based on boosting the immune response and combating the ITM, SK/siTGF-β NPs would be a potential approach for TNBC therapy.
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Feng W, Shi W, Liu S, Liu H, Liu Y, Ge P, Zhang H. Fe(III)-Shikonin Supramolecular Nanomedicine for Combined Therapy of Tumor via Ferroptosis and Necroptosis. Adv Healthc Mater 2022; 11:e2101926. [PMID: 34738742 DOI: 10.1002/adhm.202101926] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/26/2021] [Indexed: 01/15/2023]
Abstract
Most of the antitumor chemotherapeutic drugs execute the therapeutic performance upon eliciting tumor cell apoptosis, which may cause chemoresistance of tumors. Design of novel drugs to eradicate apoptosis-resistant tumors via non-apoptotic cell death pathways is promising for improving the long-term chemotherapeutic efficacy. Herein, a Fe(III)-Shikonin metal-polyphenol-coordinated supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis is designed. The construction of the nanomedicine based on the coordinated self-assembly between Fe3+ and Shikonin not only overcomes the shortcomings of Shikonin including its low bioavailability and high toxicity toward normal tissues, but also integrates the theranostics functions of Fe ions. Under the exposure of the high concentration of glutathione (GSH) in tumor cells, the as-prepared nanomedicine will disassemble into Fe2+ and Shikonin, followed by stimulating the tumor cell death through ferroptosis and necroptosis. In addition, benefiting from the stealth effect of polyethylene glycol (PEG) and the targeting ability of cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) to αv β3 -integrin, NH2 -PEG-cRGD-modified nanomedicine exhibits a GSH-responsive therapy toward 4T1 tumor in vivo and self-enhanced longitudinal relaxation (T1 )-weighted imaging property. Since the self-assembly of natural Shikonin and human body-necessary Fe element is facile and feasible, the work may provide a promising supramolecular nanomedicine for next-generation chemotherapeutic applications.
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Affiliation(s)
- Wenjie Feng
- State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University Changchun 130012 P. R. China
| | - Wanrui Shi
- State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University Changchun 130012 P. R. China
| | - Shuwei Liu
- Joint Laboratory of Opto‐Functional Theranostics in Medicine and Chemistry The First Hospital of Jilin University Changchun 130021 P. R. China
| | - Huiwen Liu
- Joint Laboratory of Opto‐Functional Theranostics in Medicine and Chemistry The First Hospital of Jilin University Changchun 130021 P. R. China
| | - Yi Liu
- State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University Changchun 130012 P. R. China
- Joint Laboratory of Opto‐Functional Theranostics in Medicine and Chemistry The First Hospital of Jilin University Changchun 130021 P. R. China
| | - Pengfei Ge
- Department of Neurosurgery The First Hospital of Jilin University Changchun 130021 P. R. China
| | - Hao Zhang
- State Key Laboratory of Supramolecular Structure and Materials College of Chemistry Jilin University Changchun 130012 P. R. China
- Joint Laboratory of Opto‐Functional Theranostics in Medicine and Chemistry The First Hospital of Jilin University Changchun 130021 P. R. China
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Sun Q, Wu J, Zhu G, Li T, Zhu X, Ni B, Xu B, Ma X, Li J. Lactate-related metabolic reprogramming and immune regulation in colorectal cancer. Front Endocrinol (Lausanne) 2022; 13:1089918. [PMID: 36778600 PMCID: PMC9909490 DOI: 10.3389/fendo.2022.1089918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023] Open
Abstract
Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.
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Affiliation(s)
- Qianhui Sun
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingyuan Wu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Guanghui Zhu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Tingting Li
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiaoyu Zhu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baoyi Ni
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bowen Xu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xinyi Ma
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Li
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Jie Li,
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