Immune checkpoint inhibitors (ICIs) have revolutionized the way cancer is treated by engaging the patient's own immune system to attack cancer. ICIs can also achieve favorable outcomes in patients whose cancers are unresponsive or resistant to first-line therapies. Despite these exciting prospects, ICIs are ineffective in many patients and cause immune-related adverse events (irAEs) in up to 89 % of patients. Therefore, there is a clear clinical need to reduce irAEs while maintaining or improving the therapeutic efficacy of ICIs. The local administration of ICIs through intratumoral injection or peritumoral administration has been shown to increase the potency of these therapeutics while reducing irAEs and extending survival in preclinical models. However, the rapid systemic distribution of intratumorally delivered drugs (hours) prevents this strategy from achieving even better efficacy and reduced toxicity; this is particularly problematic for ICIs due to their long biological (weeks), consequently acting at non-target sites for weeks before being cleared by the body. Engineered biomaterials have the potential to enhance local administration by improving permeation and retention, employing antibody-mediated targeting, leveraging tumor microenvironment sense-and-respond systems, or taking advantage of cell trafficking. This paper reviews the cutting-edge delivery strategies shown to improve the safety and efficacy of drugs targeting PD-1, PD-L1, and CTLA-4 and identifies the most promising strategies for clinical translation.

Ubiquitin-conjugating enzyme E2 C (UBE2C) is involved in tumor progression and cellular processes in many cancers and is implicated in cell cycle regulation. However, its prognostic significance in Hepatocellular carcinoma (HCC) and the mechanism of tumor immune response are unknown. The expression of UBE2C genes in HCC and normal tissue samples was investigated based on The Cancer Genome Atlas (TCGA) LIHC dataset and validated by Gene Expression Omnibus and Human Protein Atlas. Subsequently, the relationship between UBE2C gene expression, clinicopathologic parameters, and each survival period was investigated by regression analysis and Kaplan-Meier survival curves. The set of genes co-expressed with UBE2C was constructed and subjected to genomic enrichment analysis, GO and KEGG pathway enrichment analysis. Finally, the relationship between UBE2C gene expression and immune cell infiltration, immunosuppressive molecules in tumor samples from the TCGA-LIHC dataset was investigated. UBE2C gene expression levels were significantly higher in HCC samples compared to normal samples (p < 0.05). Higher UBE2C gene expression was closely associated with higher tumor grade and later tumor stage. The results of Kaplan-Meier survival curves showed that the survival of HCC patients with high UBE2C expression was shorter than that of patients with low UBE2C expression (p < 0.05, HR(CI) = 1.870[1.276, 2.741]). The results of PPI showed a high correlation between cell cycle-related proteins and UBE2C gene expression. Additionally, the highly expressed UBE2C gene was associated with an increased number of immunosuppressive molecules. UBE2C is an independent predictive marker for HCC patients, and the prognostic value of survival is improved when combined with clinical stage information. This study reveals its potential as a prognostic biomarker and as a new target for HCC intervention.

The improvement of the prediction of prostate cancer (PCa) is a major challenge in disease management. This study analysed a total of 147,856 cells and identified 15 distinct cell types using single-cell RNA-sequencing (scRNA-seq) and bulk RNA-seq data from TCGA and GEO databases. Of these cells, 31,256 exhibited a high telomere-related gene score and were predominantly composed of myeloid dendritic cells (mDCs). Simultaneously, pseudo-temporal analysis indicated that mDCs are in the later stages of the differentiation trajectory, suggesting the significant role of mDCs as telomere-active cells in the development of PCa. Analysis of cell-cell communication revealed significant differences, particularly an increase in communication between mDCs and CTLs, alongside a decrease in communication between mDCs and B cells. These variations may represent critical nodes influencing the development of PCa. Additionally, two hub genes were utilized to create risk models, with ROC curves confirming their predictive efficacy for 3-, 5-, and 10-year survival rates in patients. Functional analysis of these genes was conducted, and NPY siRNA transfection notably inhibited proliferation in LNCaP and DU145 cells. Furthermore, the models demonstrated that high-risk patients had poorer overall survival, greater immune infiltration, and reduced sensitivity to chemotherapeutic drugs.

Abundant ·OH, 1O2, and ·O2- provide an efficient methodology for rapid tumor and bacteria killing, whereas a limitation focuses on the catalytic efficiency. Thus, Jahn-Teller-driven electronic modulation of a bioheterojunction (bioHJ) platform is developed for the remedy in diabetic infectious wound regeneration after postoperative tumor resection. The bioHJ is composed of MoTe2/MnO2 and glucose oxidase (GOx). GOx depletes glucose to H2O2, which intercepts their glucose metabolism. The H2O2 can be further converted into highly lethal ·OH owing to peroxidase-mimetic activity via the Jahn-Teller effect, while GSH can be consumed due to its GPx-mimetic activity. Both of which can be further amplified upon NIR irradiation as NIR-activatable enzyme-mimetic activities. In vivo studies in a subcutaneous tumor model and infectious model authenticate the ability to kill tumor, defeat bacterial infection, and accelerate wound regeneration. This work enlightens a powerful platform for postoperative infectious wound regeneration of tumor resection using an engineered bioHJ.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need to enhance immune checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role in immune checkpoint regulation, directly impacting the expression and function of these key proteins. This review delves into the influence of significant PTMs-ubiquitination, phosphorylation, and glycosylation-on immune checkpoint signaling. By targeting these modifications, novel immunotherapeutic strategies have emerged, paving the way for advancements in optimizing immune checkpoint blockade therapies in the future.

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.

Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles.

A lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays.

NETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo.

NET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.

The management and treatment of tumor complications pose continuous challenges due to the inherent complexity. However, the advent of drug delivery systems (DDSs) brings promising opportunities to address the tumor complications using innovative technological approaches. This review focuses on common oncological complications, including cancer thrombosis, malignant serous effusion, tumor-associated infections, cancer pain, and treatment-related complications. Emphasis was placed on the application and potential of DDSs in mitigating and treating these tumor complications, and we delved into the underlying mechanisms of common cancer-associated complications, discussed the limitations of conventional treatments, and outlined the current status and potential development of DDSs for various complications in this review. Moreover, we have discussed the existing challenges in DDSs research, underscoring the need for addressing issues related to biocompatibility and targeting of DDSs, optimizing drug delivery routes, and enhancing delivery efficiency and precision. In conclusion, DDSs offer promising avenues for treating cancer complications, offering the potential for the development of more effective and safer drug delivery strategies, thereby improving the quality of life and survival rates of cancer patients.

Colorectal cancer (CRC) remains a serious threat to humans worldwide. In this study, we used bibliometric analysis of the scientific literature to assess the trends and prospects of nanotechnology applications in CRC.

We used the Web of Science Core Collection database to screen relevant publications on nanotechnology and CRC from 2004 to 2023 based on the inclusion criteria. Bibliometric analyses were performed on all selected publication and citation data. Visual analysis using VOSviewer and CiteSpace intuitively reflected the hotspots in this field.

In total, 2040 publications on nanotechnology in CRC were identified for this two-decade analysis. China (443, 29.14%) and the USA (199, 13.09%) were the top two most productive countries, and Sichuan University was the most prolific institution. The most influential journal was the International Journal of Nanomedicine. The author with the most papers was Li L. "Nanoparticles," "drug delivery," and "CRC" were the most common keywords. Green synthesis and gold nanoparticles were peripheral, incompletely developed topics.

This study provides a comprehensive overview of nanomaterials in CRC as clinical medicine, enriching the body of evidence in this field.

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.

Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP5k nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP5k was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.

Chemotherapy resistance in triple-negative breast cancer (TNBC) leads to poor therapeutic effects and a poor prognosis. Given that paclitaxel-based chemotherapy is the main treatment method for TNBC, enhancing its chemosensitivity has been a research focus. Induced ferroptosis of tumour cells has been proven to increase chemosensitivity, but its ability to sensitize TNBC cells to paclitaxel (PTX) is unknown. In our experiments, measurements of viability and proliferation validated the synergistic effect of PTX combined with RSL3 on TNBC cells. The accumulation of intracellular Fe2+ and lipid reactive oxygen species, as well as the expression of malondialdehyde, illustrated that RSL3 enhanced the chemosensitivity of TNBC to PTX by inducing ferroptosis. Through transcriptome sequencing, a series of differentially expressed genes were identified, in which the expression of cytokines, such as CXCLs, was significantly increased in the treatment group, and the effect of combination therapy on TNBC was enriched mainly in the NFκB signalling pathway. In subsequent validation experiments, the use of the NF-κB inhibitor BAY11-7082 reversed the inhibitory effects of PTX and RSL3 on TNBC cell activity. In a xenograft immunodeficient mouse model, the inhibitory effects of PTX and RSL3 on TNBC in vivo were further verified. Our research validated the synergistic effects of PTX and RSL3 both in vivo and in vitro, with RSL3 inducing ferroptosis by activating the NF-κB signalling pathway, thereby increasing the chemosensitivity of TNBC to PTX. This study provides new insights for improving the therapeutic efficacy of treatment strategies.

The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

DNA's extraordinary potential reaches far beyond its role as a carrier of genetic information. It serves as a remarkably adaptable structural foundation for constructing intricate nanostructures with a diverse range of functionalities. This inherent programmability sets DNA apart from other biomolecules like peptides, proteins, and small molecules. By covalently attaching DNA to synthetic hydrophobic moieties, researchers create DNA amphiphiles capable of interacting with artificial lipid bilayers and cell membranes. These hybrid structures have rapidly gained prominence due to their promising potential in the medical field. This review provides a comprehensive overview of the latest advancements in the synthesis of DNA amphiphiles and their assembly into well-defined nanostructures. It explores the diverse applications of these nanostructures across various medical domains, including targeted drug delivery, innovative immunotherapies, and gene-silencing techniques. Moreover, the review delves into the current challenges and prospects of this rapidly evolving field, highlighting the potential of DNA hybrid materials to revolutionize medical treatments and diagnostics. By addressing the limitations and exploring new avenues of research, scientists aim to unlock the full potential of DNA nanotechnology for the benefit of human health.

Photodynamic therapy (PDT) combined with immunotherapy has become a promising antitumor strategy. However, precise regulation of the activation of antitumor immunity and effective reversion of immunosuppressive tumor microenvironment (TME) remains challenging. In this paper, a novel co-delivery nanomedicine is developed to solve these issues for photodynamic amplified immunotherapy. Specifically, the glycolysis inhibitor (Lon) is coupled with PD1/PDL1 blocker (BMS-1) by thioketal linkage to form smartly responsive prodrug LTB, which could further encapsulate photosensitizer chlorine e6 (Ce6) to construct a co-delivery nanoplatform (LTB-6 NPs) by self-assembly. Of note, LTB-6 NPs possess favorable stability, uniform morphology and improved cellular uptake. More importantly, LTB-6 NPs are capable of inhibiting glycolysis and blocking PD1/PDL1, which could greatly improve the immunosuppressive TME to promote immune activation. LTB-6 NPs-mediated PDT not only inhibits tumor proliferation but also induces ICD response to activate immunological cascade. In vivo experiments indicate that intravenously injected LTB-6 NPs remarkably suppresses the tumor growth while leads to a minimized side effect. This research provides a multi-synergized strategy for developing effective photodynamic nanoplatforms in tumor treatment.

Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection. We highlight several key studies and future directions of research in relation to anti-PD-1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV-specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti-PD-1 and anti-CTLA-4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti-PD-1 in vivo in people with HIV on ART without cancer and potential combinations of anti-PD-1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers.

The 5-year survival rate for ovarian cancer has remained relatively static over the past number of years, which can be attributed in part to the lack of new therapeutic strategies to target this disease. Although numerous other cancer types have benefited from the success of immune checkpoint inhibitors, their use in clinical trials targeting ovarian cancer has shown limited efficacy. Most clinical trials have focused on PD-1/PD-L1 immune checkpoint blockade, either as a monotherapy or in combination with chemotherapies, however inhibiting other pathways may potentially be more efficacious in treating ovarian cancer. For example, drugs targeting some emerging immune checkpoints (such as LAG-3, TIM-3, TIGIT and PVRIG), are entering into clinical trials, which could show improved success for ovarian cancer patients. Similarly, predictive biomarkers that have been approved for use with immune checkpoint inhibitors, such as PD-L1 expression, are limited, as only the presence or absence of PD-L1 is assessed. However, the development of next generation predictive biomarkers, which assesses density and location of tumour infiltrating lymphocytes, could be more beneficial for this heterogenous cancer. In this review we discuss the use of immune checkpoint inhibitors in ovarian cancer, with a focus on high-grade serous disease, and delve into what the future may hold for immunotherapy in this cancer type.

Local immunotherapy represents a promising solution for preventing tumor recurrence and metastasis post tumor surgical resection by eliminating residue tumor cells as well as eliciting tumor-specific immune responses. Minimally invasive surgery has become a mainstream surgical method worldwide due to its advantages of aesthetics and rapid postoperative recovery. Unfortunately, the currently reported local immunotherapy strategies are mostly designed to be used after open laparotomy, which go against the current surgical philosophy of minimally invasive therapy and is not suitable for clinical translation. Aiming at this problem, a minimally invasive injectable gel (MIGel) is herein reported loaded with immunotherapeutic agents for gastric and liver cancer postoperative treatment. The MIGel is formed by crosslinking between oxidized dextran (ODEX) and 4-arm polyethylene glycol hydroxylamine (4-arm PEG-ONH2) through oxime bonds, which can be injected through a clinic-used minimally invasive drainage tube and adhered tightly to the tissue. The loaded oxaliplatin (OxP) and resiquimod (R848) can be released constantly over two weeks and resulted in over 75% cure rate in orthotopic mouse gastric and liver cancer model. Collectively, a concept of minimally invasive local immunotherapy is proposed and MIGel is designed for local intraperitoneal cancer immunotherapy through minimally invasive surgery, with good clinical translation potential.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is characterized by persistent and recurrent gastrointestinal inflammation. Conventional IBD therapies often involve the use of antibiotics, NSAIDs, biological agents, and immunomodulators. While these medications can mitigate acute inflammatory symptoms, their long-term efficacy is frequently compromised due to cumulative toxic effects. In recent years, significant attention has shifted toward nanoparticle (NP)-based therapies as potential alternatives for IBD management. Various drug delivery strategies, including those targeting microbiota interactions, ligand-receptor binding, pH sensitivity, biodegradability, pressure response, and specific charge and size parameters, have been explored and optimized in animal studies. This review provides a comprehensive overview of the current landscape of chitosan NP-mediated drug delivery systems for IBD treatment. Additionally, it will discuss the prevailing challenges and propose future research directions to advance chitosan NP-based therapeutic strategies for IBD.

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON's large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON's rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the ''cold tumor'' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy. Furthermore, the occurrence of immune-related adverse events (iRAEs) often necessitates the use of sub-therapeutic doses or treatment discontinuation. In the pursuit of innovative approaches to enhance the effectiveness of immunotherapy for PC, implantable drug delivery devices and scaffolds emerge as promising strategies. These technologies offer the potential for sustained drug delivery directly to the tumor site, overcoming stromal barriers, immunosuppression, T cell exclusion, immunotherapy resistance, optimizing drug dosage, and mitigating systemic toxicity. This review offers a comprehensive exploration of pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of PC, accompanied by a critical analysis of the challenges the microenvironment presents to the development of successful combinational immunotherapy approaches. Despite efforts, these approaches have thus far fallen short in enhancing treatment outcomes for PDAC. The review will subsequently delve into the imperative need for refining delivery strategies, providing an examination of past and ongoing studies in the field of localized immunotherapy for PDAC. Addressing these issues will lay the groundwork for the development of effective new therapies, thereby enhancing treatment response, patient survival, and overall quality of life for individuals diagnosed with PDAC.

The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp.) or probiotics (Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum-infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8+ T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome-immunotherapy interventions.

The prospect of employing chemoimmunotherapy targeted towards the endoplasmic reticulum (ER) presents an opportunity to amplify the synergistic effects of chemotherapy and immunotherapy. In this study, we initially validated celastrol (CEL) as an inducer of immunogenic cell death (ICD) by promoting ER stress and autophagy in colorectal cancer (CRC) cells. Subsequently, an ER-targeted strategy was posited, involving the codelivery of CEL with PD-L1 small interfering RNAs (siRNA) using KDEL peptide-modified exosomes derived from milk (KME), to enhance chemoimmunotherapy outcomes. Our findings demonstrate the efficient transportation of KME to the ER via the Golgi-to-ER pathway. Compared to their non-targeting counterparts, KME exhibited a significant augmentation of the CEL-induced ICD effect. Additionally, it facilitated the release of danger signaling molecules (DAMPs), thereby stimulating the antigen-presenting function of dendritic cells and promoting the infiltration of T cells into the tumor. Concurrently, the ER-targeted delivery of PD-L1 siRNA resulted in the downregulation of both intracellular and membrane PD-L1 protein expression, consequently fostering the proliferation and activity of CD8+ T cells. Ultimately, the ER-targeted formulation exhibited enhanced anti-tumor efficacy and provoked anti-tumor immune responses against orthotopic colorectal tumors in vivo. Collectively, a robust ER-targeted delivery strategy provides an encouraging approach for achieving potent cancer chemoimmunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and been extensively used for patients with metastastic colorectal cancer (mCRC), especially those harboring deficient mismatch repair/ microsatellite instability (dMMR/MSI). However, the majority of mCRC are classified as proficient mismatch repair/microsatellite stability(pMMR/MSS) type characterized by a cold immune microenvironment, rendering them generally unresponsive to ICIs. How to improve the efficacy of ICIs for these patients is an important issue to be solved. On the one hand, it is urgent to discover the predictive biomarkers and clinical characteristics associated with effectiveness and expand the subset of pMMR/MSS mCRC patients who benefit from ICIs. Additionally, combined strategies are being explored to modulate the immune microenvironment of pMMR/MSS CRC and facilitate the conversion of cold tumors into hot tumors. In this review, we have focused on the recent advancements in the predictive biomarkers and combination therapeutic strategies with ICIs for pMMR/MSS mCRC.

Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory condition characterized by recurring inflammation of the intestinal mucosa. However, the existing IBD treatments are ineffective and have serious side effects. The etiology of IBD is multifactorial and encompasses immune, genetic, environmental, dietary, and microbial factors. The nanoparticles (NPs) developed based on specific targeting methodologies exhibit great potential as nanotechnology advances. Nanoparticles are defined as particles between 1 and 100 nm in size. Depending on their size and surface functionality, NPs exhibit different properties. A variety of nanoparticle types have been employed as drug carriers for the treatment of inflammatory bowel disease (IBD), with encouraging outcomes observed in experimental models. They increase the bioavailability of drugs and enable targeted drug delivery, promoting localized treatment and thus enhancing efficacy. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery strategies, and screen new nanomedicines.

Despite cisplatin's pivotal role in clinically proven anticancer drugs, its application has been hampered by severe side effects and a grim prognosis. Herein, we devised a glutathione (GSH)-responsive nanoparticle (PFS-NP) that integrates a disulfide bond-based amphiphilic polyphenol (PP-SS-DA), a dopamine-modified cisplatin prodrug (Pt-OH) and iron ions (Fe3+) through coordination reactions between Fe3+ and phenols. After entering cells, the responsively released Pt-OH and disulfide bonds eliminate the intracellular GSH, in turn disrupting the redox homeostasis. Meanwhile, the activated cisplatin elevates the intracellular H2O2 level through cascade reactions. This is further utilized to produce highly toxic hydroxyl radicals (˙OH) catalyzed by the Fe3+-based Fenton reaction. Thus, the amplified oxidative stress leads to immunogenic cell death (ICD), promoting the maturation of dendritic cells (DCs) and ultimately activating the anti-tumor immune system. This innovative cisplatin prodrug nanoparticle approach offers a promising reference for minimizing side effects and optimizing the therapeutic effects of cisplatin-based drugs.

The tumor microenvironment (TME) exerts an important role in carcinogenesis and progression. Several investigations have suggested that immune cell infiltration (ICI) is of high prognostic importance for tumor progression and patient survival in many tumors, particularly prostate cancer. The pattern of immune infiltration of PCa, on the other hand, has not been thoroughly understood.

The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets on PCa were obtained, and several datasets were merged into one data set using the "ComBat" algorithm. The ICI profiles of PCa patients were then to be uncovered by two computer techniques. The unsupervised clustering method was utilized to identify three ICI patterns in tumor samples, and Principal Component Analysis (PCA) was conducted to estimate the ICI score.

Three different clusters of three ICIs were identified in 1341 PCa samples, which also correlated with different clinical features/characteristics and biological pathways. Patients with PCa are classified into high and low subtypes based on the ICI scores extracted from immune-associated signature genes. High ICI score subtypes are associated with a worse prognosis, which may intrigue the activation of cancer-related and immune-related pathways such as pathways involving Toll-like receptors, T-cell receptors, JAK-STAT, and natural killer cells. The ICI score was linked to tumor mutation load and immune/cancer-relevant signaling pathways, which explain prostate cancer's poor prognosis.

The findings of this study not only advanced our knowledge of the mechanism of immune response in the prostate tumor microenvironment but also provided a novel biomarker, that is, the ICI score, for disease prognosis and guiding precision immunotherapy.

Colorectal cancer (CRC) is the most common type of newly diagnosed cancer. Metastatic spread and multifactorial chemoresistance have limited the benefits of current therapies. Hence, it is imperative to identify new therapeutic agents to increase treatment efficacy. One of CRC's most promising immunotherapeutic targets is programmed death-1 (PD-1), a cell surface receptor that regulates immune responses. In this paper, we provide an overview of the therapeutic impact of PD-1 in the treatment of CRC. Cancer cells can exploit the PD-1 pathway by upregulating its programmed death-ligand 1 (PD-L1) ligand to evade immune surveillance. The binding of PD-L1 to PD-1 inhibits T cell function, leading to tumor immune escape. PD-1 inhibitors, such as pembrolizumab and nivolumab, block the PD-1/PD-L1 interaction. Clinical trials evaluating PD-1 inhibitors in advanced CRC have shown promising results. In patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors characterized by high mutation rates and increased immunogenicity, PD-1 blockade has demonstrated remarkable efficacy. As a result, pembrolizumab and nivolumab have received accelerated approval by regulatory authorities for the treatment of MSI-H/dMMR metastatic CRC. Additionally, combination approaches, such as combining PD-1 inhibitors with other immunotherapies or targeted agents, are being explored. Despite the success of PD-1 inhibitors in CRC, challenges still exist. Immune-related adverse events can occur and require close monitoring. In conclusion, PD-1 inhibitors have demonstrated significant therapeutic impact, particularly in patients with MSI-H/dMMR tumors.

Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson's trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-β1, and α-SMA) and epithelial-mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-β1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.

The functional relevance of cyclic adenosine monophosphate (cAMP)-response element-binding protein 5 (CREB5) in cancers remains elusive, despite its significance as a member of the CREB family. The current research aims to explore the role of CREB5 in multiple cancers.

Pan-cancer analysis was performed to explore the expression patterns, prognostic value, mutational landscape as well as single-cell omic, immunologic, and drug sensitivity profiles of CREB5. Furthermore, we incorporated five distinct machine learning algorithms and determined that the least absolute shrinkage and selection operator-COX (LASSO-COX) algorithm, which exhibited the highest C index, was the optimal selection. Subsequently, we constructed a prognostic model centered around CREB5-associated genes. To elucidate the biological function of CREB5 in glioma cells, several assays including cell counting kit-8 (CCK-8), wound healing, transwell, flow cytometric were performed.

CREB5 was overexpressed in pan-cancer and was linked to unfavorable prognosis, particularly in glioma. Furthermore, genetic alterations were determined in various types of cancer, and modifications in the CREB5 gene were linked to the prognosis. The single-cell omics and enrichment analyses showed that CREB5 was predominantly expressed in malignant glioma cells and was critically involved in the regulation of various oncogenic processes. Elevated levels of CREB5 were strongly linked with the infiltration of cancer-associated fibroblasts and the Th1 subset of CD4+ T cells. The validated CREB5-associated prognostic model reliably predicted the prognosis and drug response of glioma patients. The in vitro experiments showed that CREB5 promoted glioma cell proliferation, invasion, migration, and gap phase 2/mitotic (G2/M) phase arrest and recruited M2 macrophages into glioma cells.

CREB5 has the potential to act as an oncogene and a biological marker in multiple cancers, particularly glioma.

Cancer is a growing worldwide health problem with the most broadly studied treatments, in which immunotherapy has made notable advancements in recent years. However, innumerable patients have presented a poor response to immunotherapy and simultaneously experienced immune-related adverse events, with failed therapeutic results and increased mortality rates. Consequently, it is crucial to develop alternate tactics to boost therapeutic effects without producing negative side effects. Ultrasound is considered to possess significant therapeutic potential in the antitumor field because of its inherent characteristics, including cavitation, pyrolysis, and sonoporation. Herein, this timely review presents the comprehensive and systematic research progress of ultrasound-enhanced cancer immunotherapy, focusing on the various ultrasound-related mechanisms and strategies. Moreover, this review summarizes the design and application of current sonosensitizers based on sonodynamic therapy, with an attempt to provide guidance on new directions for future cancer therapy.

Camptothesome is a sphingomyelin-conjugated camptothecin (SM-CSS-CPT) nanovesicle that fortified the therapeutic delivery of CPT in diverse cancer types. To mitigate the Camptothesome-induced IDO1 negative feedback mechanism, we had co-encapsulated, indoximod (IND, IDO1 inhibitor) into Camptothesome using doxorubicin-derived IND (DOX-IND). To maximize the therapeutic potential of DOX-IND/Camptothesome, herein, we first dissected the synergistic drug ratio (DOX-IND/SM-CSS-CPT) via systematical in vitro screening. DOX-IND/Camptothesome with optimal drug ratio synchronized in vivo drug delivery with significantly higher tumor uptake compared to free drugs. This optimum DOX-IND/Camptothesome outperformed the combination of Camptothesome, Doxil and IND or other IDO1 inhibitors (BMS-986205 or epacadostat) in treating mice bearing late-stage MC38 tumors, and combination with immune checkpoint blockade (ICB) enabled it to eradicate 60 % of large tumors. Further, this optimized co-delivery Camptothesome beat Folfox and Folfiri, two first-line combination chemotherapies for colorectal cancer in antitumor efficacy and exhibited no side effects as compared to the severe systemic toxicities associated with Folfox and Folfiri. Finally, we demonstrated that the synergistic DOX-IND/Camptothesome was superior to the combined use of Onivyde + Doxil + IND in curbing the advanced orthotopic CT26-Luc tumors and eliminated 40 % tumors with complete metastasis remission when cooperated with ICB, eliciting stronger anti-CRC immune responses and greater reversal of immunosuppression. These results corroborated that with precise optimal synergistic drug ratio, the therapeutic potential of DOX-IND/Camptothesome can be fully unleased, which warrants further clinical investigation to benefit the cancer patients.