Swertianolin is one of the main components of Gentianaceae Swertia plants, a traditional Chinese medicine used for the treatment of infection, fever, viral hepatitis, and pneumonia. An expansion of myeloid-derived suppressor cells (MDSCs) contributes to sepsis induced immunosuppression. We investigated the mechanism by which Swertianolin regulates MDSCs in a mouse model of sepsis.

Severe sepsis was induced in mice using caecal ligation and puncture. These mice received an intraperitoneal injection of Swertianolin. MDSCs were isolated and analyzed by flow cytometry; serum concentrations of immunosuppressive factors were detected by ELISA; and mitogen-activated protein kinase and nuclear factor-κB (NFκB) were detected by Western blots.

We found that Swertianolin reduced the number of MDSCs in the marrow and the spleen while increased the number of CD4+ T cells in the spleen of mice with sepsis in comparison to controls (p < 0.05). Swertianolin reduced lung damage and improved the survival rate in mice with secondary infection of Legionella pneumophila (p < 0.05). Swertianolin inhibited the phosphorylation of p38 and nuclear translocation of p65 in MDSCs (p < 0.05), leading to decreased production of IL-10 and nitric oxide (both p < 0.05).

Swertianolin may improve immunosuppressive function of MDSCs and increased T cell activity by inhibiting p38 phosphorylation and NF-κB activation.

With the rise of immunotherapy, the treatment approach for non-small cell lung cancer (NSCLC) has undergone revolutionary changes. However, the prognosis for NSCLC patients has not been significantly improved due to the development of acquired drug resistance. Therefore, there is an urgent need to develop new and more effective drugs for treating NSCLC or improving tumor treatment resistance. Traditional Chinese medicine (TCM) has been gradually incorporated into the combined treatment of NSCLC. Its active components (also known as natural products) exhibit novel structures, multi-target effects, diverse pathways, minimal toxicity, and varied biological activities, which play a therapeutic role in various diseases. Thus, natural products hold great potential for future clinical applications.

Screening main traditional plants widely used in NSCLC and their derived natural products, as well as exploring the mechanisms by which these natural products act on NSCLC-particularly focusing on their applications-can provide valuable insights for the development of therapeutic drugs targeting NSCLC.

A comprehensive, computerized literature search was conducted in PubMed, Embase, Web of Science, Cochrane Library, CNKI Scholar, the American Chemical Abstracts, and Wanfang Database up to June 2024, using the following keywords: "traditional Chinese medicine", "herbal medicine", "medicinal plants", and "herbal", paired with terms such as "non-small cell lung cancer", "therapy", "natural products", and "active ingredient".

Summarizing current research findings, we discovered eleven medicinal plants containing a total of fourteen natural products. Natural products have a significant impact on tumor progression in NSCLC, including apotosis, autophagy, pyrotosis, cell-cycle arrest and metasis. Moreover, natural products can modulate the activities of various immune cells and reshape the immune microenvironment. Combined with conventional cancer treatments, natural products demonstrate promising therapeutic effects and effectively reverse drug resistance. Furthermore,the use of nano-drug delivery systems to address limitations associated with natural products.

This review summarizes eleven medicinal plants containing a total of fourteen natural products that can enhance NSCLC treatment and indicates their action mechanisms. Furthermore, we also discuss limitations of natural products and explore the use of nano-drug delivery systems to address limitations associated with natural products.

Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.

Understanding the causal relationships between immune cell populations and cancer development remains a critical challenge in tumor immunology.

We employed Mendelian Randomization analysis leveraging genome-wide association studies of 612 immune cell traits and 91 cancer types to systematically evaluate causal associations. Single-cell RNA sequencing and computational deconvolution analyses were performed to characterize myeloid cell subpopulations in melanoma samples.

Our analysis revealed significant relationships between specific immune cell subsets and cancer risk, particularly highlighting the role of CD33 + myeloid cells in melanoma pathogenesis. Single-cell RNA sequencing identified distinct CD33high myeloid subpopulations characterized by elevated expression of complement cascade components and chemokine signaling pathways. Through computational deconvolution of The Cancer Genome Atlas melanoma cohort, we demonstrated that elevated CD33high monocyte abundance correlates with increased immune dysfunction scores, reduced CD8 + T cell infiltration, and poor survival outcomes.

Here we delineate the multifaceted mechanisms through which CD33 + myeloid cell populations orchestrate perturbations in the tumor-immune microenvironmental landscape, manifesting in compromised immunosurveillance and enhanced tumor progression. Our findings illuminate novel therapeutic opportunities through targeted modulation of myeloid cell function, while providing a systematic framework for understanding the complex interplay between immune cell populations and oncogenic processes.

Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system. Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut-retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity. In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.

Myeloid-derived suppressor cells (MDSCs) regulate immune responses in many pathological conditions, one of which is inflammatory bowel disease (IBD), an incurable chronic disorder of the digestive tract and beyond. The pathophysiology of IBD remains unclear, likely involving aberrant innate and adaptive immunity. Studies have reported altered population of MDSCs in patients with IBD. However, their distribution varies among patients and different preclinical models of IBD. The expansion and activation of MDSCs are likely driven by various stimuli during intestinal inflammation, but the in-depth mechanisms remain poorly understood. The role of MDSCs in the pathogenesis of IBD appears to be paradoxical. In addition to intestinal inflammation, suppressive MDSCs may promote colitis-to-colon cancer transition. In this Review, we summarize recent progresses on the features, activation, and roles of MDSCs in the development of IBD and IBD-associated colon cancer.

Despite the success of cancer immunotherapy in treating hematologic malignancies, their efficacy in solid tumors remains limited due to the immunosuppressive tumor microenvironment (TME), which is mainly formed by myeloid-derived suppressor cells (MDSCs). MDSCs not only exert potent immunosuppressive effects that hinder the success of immune checkpoint inhibitors (ICIs) and adaptive cellular therapies, but they also promote tumor advancement through non-immunological pathways, including promoting angiogenesis, driving epithelial-mesenchymal transition (EMT), and contributing to the establishment of pre-metastatic environments. While targeting MDSCs alone or in combination with conventional therapies has shown limited success, emerging evidence suggests that MDSC checkpoint blockade in combination with other immunotherapies holds great promise in overcoming both immunological and non-immunological barriers. In this review, we discussed the dual roles of MDSCs, with a particular emphasis on their underexplored checkpoints blockade strategies. We discussed the rationale behind combination strategies, their potential advantages in overcoming MDSC-mediated immunosuppression, and the challenges associated with their development. Additionally, we highlight future research directions aimed at optimizing combination immunotherapies to enhance cancer therapeutic effectiveness, particularly in solid tumor therapies where MDSCs are highly prevalent.

Extracellular vesicles (EVs), tiny packages of information released by cells, are well established as being involved in unwanted cell-to-cell communication in cancer. EVs from cancer cells have been associated with the spread of drug resistance, immune suppression, and metastasis. Additional to cancer cells, the tumour microenvironment (TME) involves many cell types -including immune cells, fibroblasts, and endothelial cells, each of which has a potential role in how tumours grow, spread, and respond (or otherwise) to therapy. This review collates and distils research developments regarding the role of EVs in multi-way communication between cells in the TME. Further research including tailored clinical studies are now warranted to determine how best to prevent this extensive adverse communication occurring and/or how best to exploit it for biomarker discovery and as a therapeutic approach, in the interest of patients and also for economic benefit.

Angiogenesis, as a core marker of cancer survival and growth, is integral to the processes of tumour growth, invasion and metastasis. In recent years, targeted angiogenesis treatment strategies have gradually become an important direction in cancer treatment. Single-cell sequencing technology can provide new insights into targeted angiogenesis by providing a deeper understanding of the heterogeneity of tumour endothelial cells and exploring the interactions between endothelial cells and surrounding cells in the tumour microenvironment. Here, we systematically review the research progress in endothelial cell pathophysiology and its endothelial‒mesenchymal transition and illustrate the heterogeneity of endothelial cells from a single-cell perspective. Finally, we examine the contributions of different cell types within the tumour microenvironment in relation to tumour angiogenesis, as well as the latest progress and strategies in targeted angiogenesis therapy, hoping to provide useful insights into the clinical application of antiangiogenic treatment. Furthermore, a summary of the present progress in the development of potential angiogenesis inhibitors and the ongoing clinical trials for combination therapies is provided. KEY POINTS: Angiogenesis plays a key role in tumour progression, invasion and metastasis, so strategies targeting angiogenesis are gradually becoming an important direction in cancer therapy. Interactions between endothelial cells and stromal cells and immune cells in the tumour microenvironment are significant in angiogenesis. The application of antiangiogenic immunotherapy and nanotechnology in antiangiogenic therapy provides a vital strategy for prolonging the survival of cancer patients.

Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1), a member of the A/B subfamily of hnRNPs, plays a critical role in tumorigenesis, yet its expression patterns, molecular mechanisms, and prognostic significance remain inadequately characterized. In this study, we performed a comprehensive pan-cancer analysis utilizing multiple public databases, revealing that HNRNPA2B1 is consistently overexpressed in most tumor types and correlates with poor prognosis across several malignancies. Pathway enrichment analysis highlighted its involvement in RNA alternative splicing, transport, and stability, processes that contribute to tumor progression. Epigenetic analyses identified gene amplification and alternative splicing as potential mechanisms driving HNRNPA2B1 overexpression. Furthermore, elevated HNRNPA2B1 levels conferred resistance to multiple chemotherapeutics, including Dasatinib. Functional studies demonstrated that HNRNPA2B1 enhances lung cancer cell proliferation and migration by upregulating TARDBP and cell cycle-related genes, with m6A modification serving as a critical regulatory mechanism. Collectively, these findings establish HNRNPA2B1 as an oncogenic factor across multiple cancer types, underscoring its value as a prognostic marker and a promising therapeutic target, particularly in lung cancer, offering new insights for targeted therapeutic strategies.

Recent research highlights the pivotal role of N6-methyladenosine (m6A) modification and ferroptosis in the evolution of various cancers. This study aimed to establish a prognostic framework centered on genes associated with m6A and ferroptosis to enhance the accuracy of prognosis predictions for neuroblastoma (NB) patients, thereby improving targeted therapeutic strategies. Patient data, including expression profiles and clinical information from NB cases, were acquired from The Cancer Genome Atlas. Genes related to m6A modification and ferroptosis were identified, and those significant for prognosis were pinpointed using a combination of Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression. For further validation, the study utilized external datasets GSE62564 and GSE85047. A prognostic index was computed for each NB patient, followed by analyses of immune cell infiltration and potential drug responsiveness based on the prognostic model. Additionally, enrichment analysis was conducted on the prognostic scores. These scores showed a strong association with the tumor immune environment and the efficacy of prevalent cancer therapies. Moreover, the model's prognostic score emerged as an independent predictive marker for NB. This research succeeded in creating and confirming a prognostic model rooted in m6A and ferroptosis-linked genes, promising to enrich the prognostic understanding and treatment approaches for NB.

As a type of "cold tumor" with limited immune cell infiltration, ovarian cancer has historically shown limited efficacy in immunotherapy. In this study, we report that exosomes from ovarian cancer can specifically target omentum which is the predilection site for ovarian cancer to metastasize and combat subsequently implanted tumor. Furthermore, we found a substantial increase in the proportion of CD3 + T cells, particularly CD8 + T cells, within the omental tissue where exosomes homed. This increase was accompanied by a significant enhancement in granzyme B levels within CD8 + T cells. Additionally, there was a notable elevation in the concentration of interferon-gamma (IFN-γ) in peripheral blood. In vitro results indicated that exosomes could be internalized by dendritic cells (DCs), promote DC differentiation, and subsequently induce the production of granzyme B and IFN-γ in T cells. Surprisingly, we also observed high expression of programmed death ligand 1 (PD-L1) in the omentum. Therefore, we discovered whether combining PD-L1 blockade led to further tumor regression. However, although the combination group showed complete tumor regression, this difference did not reach statistical significance. But in general, we emphasize that in the case of pre-injection, exosomes have great potential to combat the famous "cold tumor", ovarian cancer, via targeting omentum and activating anti-tumor immunity, offering a novel avenue for overcoming ovarian cancer.

Head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy due to its high rates of recurrence, metastasis, and resistance to conventional therapies. microRNA-200c (miRNA-200c) has emerged as a critical tumor suppressor in HNSCC, with the potential to inhibit epithelial-mesenchymal transition (EMT), which is considered as a key process in cancer metastasis and progression. Interestingly, there are also controversial findings in HNSCC characterizing miRNA-200c as oncogenic factor. This review article provides a comprehensive overview of the current understanding of miRNA-200c's general role in cancer, and particularly in HNSCC, highlighting its mechanisms of action, including the regulation of EMT and other oncogenic pathways. Additionally, the review explores the innovative approach of exosome-mediated delivery of miRNA-200c as a therapeutic strategy. Exosomes, as natural nanocarriers, offer a promising vehicle for the targeted delivery of miRNA-200c to tumor cells, potentially overcoming the limitations of traditional delivery methods and enhancing therapeutic efficacy. The review also discusses the challenges and future directions in the clinical application of miRNA-200c, particularly focusing on its potential to improve outcomes for HNSCC patients. This article seeks to provide valuable insights for researchers and clinicians working towards innovative treatments for this aggressive cancer type.

N6-methyladenosine is one of the most common and reversible post-transcriptional modifications in eukaryotes, and it is involved in alternative splicing and RNA transcription, degradation, and translation. It is well known that cancer cells acquire energy through metabolic reprogramming to exhibit various biological behaviors. Moreover, numerous studies have demonstrated that m6A induces cancer metabolic reprogramming by regulating the expression of core metabolic genes or by activating metabolic signaling pathways. Meanwhile, m6A modifications and related regulators are key targets in the regulation of immune effects. We further summarize how m6A modifications contribute to tumor metabolism, and how these events affect the tumor immune microenvironment, with a specific focus on different cell types. Finally, we focus on the specific applications of this field to tumor immunotherapy. We review the potential role of m6A in metabolic reprogramming of tumor immune microenvironment and its regulatory mechanism, with the aim of providing new targets for tumor metabolic regulation and immunotherapy.

Non-small cell lung cancer (NSCLC) constitutes a significant proportion of lung cancer cases, and despite advancements in treatment modalities, radiotherapy resistance remains a substantial hurdle in effective cancer management. Exosomes, which are small vesicles secreted by cells, have emerged as pivotal players in intercellular communication and influence various biological processes, including cancer progression and the response to therapy. This review discusses the intricate role of exosomes in the modulation of NSCLC radiosensitivity. The paper focuses on NSCLC and highlights how tumor-derived exosomes contribute to radioresistance by enhancing DNA repair, modulating immune responses, and altering the tumor microenvironment. We further explore the potential of mesenchymal stem cell-derived exosomes to overcome radiotherapy resistance and their potential as biomarkers for predicting therapeutic outcomes. Understanding the mechanisms by which exosomes affect radiotherapy can provide new avenues for enhancing treatment efficacy and improving the survival rates of patients with NSCLC.

Chemo-immunotherapy based on inducing tumor immunogenic cell death (ICD)with chemotherapy drugs has filled the gaps between traditional chemotherapy and immunotherapy. It is verified that paclitaxel (PTX) can induce breast tumor ICD. From this basis, a kind of nanoparticle that can efficiently deliver different drug components simultaneously is constructed. The purpose of this study is for the sake of exploring the scheme of chemotherapy-induced ICD combined with other immunotherapy to enhance tumor immunogenicity and inhibit the growth, metastasis, and recurrence of breast tumors, so as to provide a research basis for solving the tough problem of breast cancer treatment.

Nanomedicine loaded with PTX, small interference RNA that suppresses CD47 expression (CD47siRNA, siCD47), and immunomodulator R848 were prepared by the double emulsification method. The hydrodynamic diameter and zeta potential of NP/PTX/siCD47/R848 were characterized. Established the tumor-bearing mice model of mouse breast cancer cell line (4T1) in situ and observed the effect of intravenous injection of NP/PTX/siCD47/R848 on the growth of 4T1 tumor in situ. Flow cytometry was used to detect the effect of drugs on tumor immune cells.

NP/PTX/siCD47/R848 nano-drug with tumor therapeutic potential were successfully prepared by double emulsification method, with particle size of 121.5 ± 4.5 nm and surface potential of 36.1 ± 2.5 mV. The calreticulin on the surface of cell membrane and extracellular ATP or HMGB1 of 4T1 cells increased through treatment with NPs. NP/PTX-treated tumor cells could cause activation of BMDCs and BMDMs. After intravenous injection, NP/PTX could quickly reach the tumor site and accumulate for 24 h. The weight and volume of tumor in situ in the breast cancer model mice injected with nanomedicine through the tail vein were significantly lower than those in the PBS group. The ratio of CD8+/CD4+ T cells in the tumor microenvironment and the percentage of dendritic cells in peripheral blood increased significantly in breast cancer model mice injected with nano-drugs through the tail vein.

Briefly, the chemotherapeutic drug paclitaxel can induce breast cancer to induce ICD. The nanomedicine which can deliver PTX, CD47siRNA, and R848 at the same time was prepared by double emulsification. NP/PTX/siCD47/R848 nano-drug can be enriched in the tumor site. The experiment of 4T1 cell tumor-bearing mice shows that the nano-drug can enhance tumor immunogenicity and inhibit breast tumor growth, which provides a new scheme for breast cancer treatment. (Graphical abstract).

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Immunotherapy, especially immune checkpoint blockade therapy, represents a major milestone in the history of cancer therapy. However, the current response rate to immunotherapy among cancer patients must be improved; thus, new strategies for sensitizing patients to immunotherapy are urgently needed. Erythroid progenitor cells (EPCs), a population of immature erythroid cells, exert potent immunosuppressive functions. As a newly recognized immunosuppressive population, EPCs have not yet been effectively targeted. In this review, we summarize the immunoregulatory mechanisms of EPCs, especially for CD45+ EPCs. Moreover, in view of the regulatory effects of EPCs on the tumor microenvironment, we propose the concept of EPC-immunity, present existing strategies for targeting EPCs, and discuss the challenges encountered in both basic research and clinical applications. In particular, the impact of existing cancer treatments on EPCs is discussed, laying the foundation for combination therapies. The aim of this review is to provide new avenues for improving the efficacy of cancer immunotherapy by targeting EPCs.

Immunotherapy has emerged as a vital component in the contemporary landscape of cancer treatment. Recent studies have indicated that CEP55 plays an oncogenic role; however, its specific mechanisms in promoting tumor proliferation and its potential value in prognosis and immunotherapy prediction across various cancers remain to be elucidated. CEP55 was significantly overexpressed in 22 cancer types compared with their adjacent normal tissues. Elevated CEP55 expression was positively correlated with younger onset age, worse tumor stage, lower response rate to the first treatment, lower tumor-free survival rate, and poorer overall survival (OS) and disease-free survival (DFS) prognosis in most cancers. Moreover, CEP55 expression was positively correlated with its binding and related genes, such as KIF11 (R = 0.83, P < 0.001), CDK1 (R = 0.77, P < 0.001) and CCNA2 (R = 0.76, P < 0.001), and the classic proliferation markers, including MKI67 and PCNA. Enrichment analyses indicated that CEP55 was predominantly associated with cell division, cell cycle activities and proliferation. Immune cell infiltration analysis by TIMER2.0 revealed that CEP55 expression was positively correlated with many kinds of infiltrating cells, such as Th2 cells and some CD4+ T cell subsets. The CEP55 expression was positively associated with increased MSI and TMB in various cancers. Our analyzation indicated that the CEP55 expression level in patients with complete remission (CR) or partial remission (PR) to anti-PDL1 therapy was significantly higher than patients with stable disease (SD) or progressive disease (PD) based on IMvigor210 cohort. We also used Gene Set Cancer Analysis (GSCA) to predict a serious of small molecule CEP55 targeted drugs, such as AZ628, SB52334, SB590885, A-770,041, AZD7762, Elesclomol, panobinostat, BRD-A94377914, and LRRK2-IN-1. Furthermore, the patients with high level of CEP55-posivie tumor epithelial cells had inferior overall survival in ccRCC according to single-cell analysis. Finally, our wet lab experiments verified that the CEP55-positive rate in ccRCC tissues (19/30, 63.3%) was significantly higher than that in renal adjacent tissues (10/30, 33.3%). The clinicopathologic analysis revealed that CEP55 protein level was significantly associated with tumor size (P = 0.044), histology grade (P < 0.001) and stage (P = 0.034). Our study indicated that CEP55 overexpression in most caner types was associated with poor prognosis. Notably, CEP55 was closely relevant to immune cell infiltration and impacted the response to immunotherapy and small molecule drugs against cancers.

Liposomal drug delivery systems have revolutionized traditional cytotoxic drugs. However, the relative instability and toxicity of the existing liposomal drug delivery systems compromised their efficacy. Herein, we present Rg3-lipo, an innovative drug delivery system using a glycosyl moiety-enriched ginsenoside (Rg3). This system is distinguished by its glycosyl moieties exposed on the liposomal surface. These moieties imitate human cell membranes to stabilize and evade phagocytic clearance. The Rg3-lipo system loaded with paclitaxel (PTX-Rg3-lipo) demonstrated favorable bioavailability and safety in Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys. With its glycosyl moieties recognizing tumor cells via the glucose transporter Glut1, PTX-Rg3-lipo inhibited gastric, breast, and esophageal cancers in human cancer cell lines, tumor-bearing mice, and patient-derived xenograft models. These glycosyl moieties selectively targeted myeloid-derived suppressor cells (MDSCs) through the glucose transporter Glut3 to attenuate their immunosuppressive effect. The mechanism study revealed that Rg3-lipo suppressed glycolysis and downregulated the transcription factors c-Maf and Mafb overcoming the MDSC-mediated immunosuppressive microenvironment and enhancing PTX-Rg3-lipo's antitumor effect. Taken together, we supply substantial evidence for its advantageous bioavailability and safety in multiple animal models, including nonhuman primates, and Rg3-lipo's dual targeting of cancer cells and MDSCs. Further investigation regarding Rg3-lipo's druggability will be conducted in clinical trials.

Copper is an important trace element for maintaining key biological functions such as cellular respiration, nerve conduction, and antioxidant defense. Maintaining copper homeostasis is critical for human health, and its imbalance has been linked to various diseases, especially cancer. Cuproptosis, a novel mechanism of copper-induced cell death, provides new therapeutic opportunities for metal ion regulation to interact with cell fate. This review provides insights into the complex mechanisms of copper metabolism, the molecular basis of cuproptosis, and its association with cancer development. We assess the role of cuproptosis-related genes (CRGs) associated with tumorigenesis, their importance as prognostic indicators and therapeutic targets, and the impact of copper homeostasis on the tumor microenvironment (TME) and immune response. Ultimately, this review highlights the complex interplay between copper, cuproptosis, and cancer immunotherapy.

N6-methyladenosine (m6A), the most abundant modification in mRNAs, affects the fate of the modified RNAs at the post-transcriptional level and participants in various biological and pathological processes. Increasing evidence shows that m6A modification plays a role in the progression of many malignancies, including colorectal cancer (CRC). As the only catalytic subunit in methyltransferase complex, methyltransferase-like 3 (METTL3) is essential to the performance of m6A modification. It has been found that METTL3 is associated with the prognosis of CRC and significantly influences various aspects of CRC, such as cell proliferation, invasion, migration, metastasis, metabolism, tumor microcirculation, tumor microenvironment, and drug resistance. The relationship between METTL3 and gut-microbiota is also involved into the progression of CRC. Furthermore, METTL3 might be a viable target for CRC treatment to prolong survival. In this review, we comprehensively summarize the function of METTL3 in CRC and the underlying molecular mechanisms. We aim to deepen understanding and offer new ideas for diagnostic biomarkers and therapeutic targets for colorectal cancer.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by persistent cognitive decline. Amyloid plaque deposition and neurofibrillary tangles are the main pathological features of AD brain, though mechanisms leading to the formation of lesions remain to be understood. Genetic efforts through genome-wide association studies (GWAS) have identified dozens of risk genes influencing the pathogenesis and progression of AD, some of which have been revealed in close association with increased viral susceptibilities and abnormal inflammatory responses in AD patients. In the present study, we try to present a list of AD candidate genes that have been shown to affect viral infection and inflammatory responses. Understanding of how AD susceptibility genes interact with the viral life cycle and potential inflammatory pathways would provide possible therapeutic targets for both AD and infectious diseases.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by producing remarkable clinical outcomes for patients with various cancer types. However, only a subset of patients benefits from immunotherapeutic interventions due to the primary and acquired resistance to ICIs. Myeloid-derived suppressor cells (MDSCs) play a crucial role in creating an immunosuppressive tumor microenvironment (TME) and contribute to resistance to immunotherapy. V-domain Ig suppressor of T cell activation (VISTA), a negative immune checkpoint protein highly expressed on MDSCs, presents a promising target for overcoming resistance to current ICIs. This article provides an overview of the evidence supporting VISTA's role in regulating MDSCs in shaping the TME, thus offering insights into how to overcome immunotherapy resistance.

Bone is a common organ affected by metastasis in various advanced cancers, including lung, breast, prostate, colorectal, and melanoma. Once a patient is diagnosed with bone metastasis, the patient's quality of life and overall survival are significantly reduced owing to a wide range of morbidities and the increasing difficulty of treatment. Many studies have shown that bone metastasis is closely related to bone microenvironment, especially bone immune microenvironment. However, the effects of various immune cells in the bone microenvironment on bone metastasis remain unclear. Here, we described the changes in various immune cells during bone metastasis and discussed their related mechanisms. Osteoblasts, adipocytes, and other non-immune cells closely related to bone metastasis were also included. This review also summarized the existing treatment methods and potential therapeutic targets, and provided insights for future studies of cancer bone metastasis.

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

In the intricate field of cancer biology, researchers are increasingly intrigued by the emerging role of exosomal long non-coding RNAs (lncRNAs) due to their multifaceted interactions, complex modulation mechanisms, and potential therapeutic applications. These exosomal lncRNAs, carried within extracellular vesicles, play a vital partin tumorigenesis and disease progression by facilitating communication networks between tumor cells and their local microenvironment, making them an ideal candidates for use in a liquid biopsy approach. However, exosomal lncRNAs remain an understudied area, especially in cancer biology. Therefore this review aims to comprehensively explore the dynamic interplay between exosomal lncRNAs and various cellular components, including interactions with tumor-stroma, immune modulation, and drug resistance mechanisms. Understanding the regulatory functions of exosomal lncRNAs in these processes can potentially unveil novel diagnostic markers and therapeutic targets for cancer. Additionally, the emergence of RNA-based therapeutics presents exciting opportunities for targeting exosomal lncRNAs, offering innovative strategies to combat cancer progression and improve treatment outcomes. Thus, this review provides insights into the current understanding of exosomal lncRNAs in cancer biology, highlighting their crucial roles, regulatory mechanisms, and the evolving landscape of therapeutic interventions. Furthermore, we have also discussed the advantage of exosomes as therapeutic carriers of lncRNAs for the development of personalized targeted therapy for cancer patients.

Osteosarcoma (OS) is the most common primary bone sarcoma with a high propensity for local invasion and metastasis. Although the antitumor effect of apatinib has been well confirmed in advanced OS, the synergistic effect of apatinib and immunotherapies has not yet been elucidated.

In this study, we established tumour-bearing mice and observed tumour size with low and high doses of apatinib treatments. The expression of 17 cytokines, including vascular endothelial growth factor (VEGF), was detected by protein microarray analysis. Moreover, we designed apatinib and antigen-specific dendritic cell (DC)-T combination treatment for tumour-bearing mice. Tumour growth was detected by statistical analysis of tumour size and microvessel density (MVD) counting, the protein expression of VEGF by western blotting, the cytokines interleukin 6 (IL-6), IL-17 and interferon-gamma (IFN-γ) by enzyme-linked immunosorbent assay (ELISA), and the numbers of myeloid-derived suppressor cells (MDSCs) and tumour-infiltration macrophages (TAMs) by flow cytometry.

The results showed that apatinib efficiently suppressed tumour growth, and high-dose apatinib achieved a stronger effect. The same was true for DC-T immunotherapy. However, their combination treatment revealed a better oncolytic effect. Meanwhile, apatinib or DC-T treatment inhibited the expression of VEGF and the proangiogenic mediators IL-6 and IL-17 but increased IFN-γ production. Combination therapy further reduced/increased these effects. In addition, the combination treatment reduced MDSC but enhanced TAM-M1 ratios in the OS microenvironment. These findings indicated that apatinib and antigen-specific DC-T combination therapy was more efficient in oncolysis by regulating pro-/anti-angiogenic inducers and improving the immune state in the OS microenvironment.

This study proved that it was feasible to employ immunotherapy with therapeutic agents in OS treatment, which may provide a new approach in addition to the combination of surgery with chemotherapy in tumour treatment.

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.

Studies have shown that adoptive transfer of myeloid-derived suppressor cells (MDSCs) can alleviate various inflammatory diseases, including glomerulonephritis, but the long-term effects of the transferred MDSCs are still unclear. In addition, although glucocorticoids exert immunosuppressive effects on inflammatory diseases by inducing the expansion of MDSCs, the impact of glucocorticoids on the immunosuppressive function of MDSCs and their molecular mechanisms are unclear. In this study, we found that adoptive transfer of MDSCs to doxorubicin-induced focal segmental glomerulosclerosis (FSGS) mice for eight consecutive weeks led to an increase in serum creatinine and proteinuria and aggravation of renal interstitial fibrosis. Similarly, 8 weeks of high-dose dexamethasone administration exacerbated renal interstitial injury and interstitial fibrosis in doxorubicin-induced mice, manifested as an increase in serum creatinine and proteinuria, collagen deposition and α-SMA expression. On this basis, we found that dexamethasone could enhance MDSC expression and secretion of the fibrosis-related cytokines TGF-β and IL-10. Mechanistically, we revealed that dexamethasone promotes the expression of immunoglobulin-like transcription factor 4 (ILT4), which enhances the T-cell inhibitory function of MDSCs and promotes the activation of STAT6, thereby strengthening the expression and secretion of TGF-β and IL-10. Knocking down ILT4 alleviated renal fibrosis caused by adoptive transfer of MDSCs. Therefore, our findings demonstrate that the role and mechanism of dexamethasone mediate the expression and secretion of TGF-β and IL-10 in MDSCs by promoting the expression of ILT4, thereby leading to renal fibrosis.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.

The α-tubulin subtype, Tubulin α-1b chain (TUBA1B), has been shown to influence immune cell infiltration, cancer growth, and survival across various malignancies. However, a comprehensive study has not yet been undertaken examining the immunological and predictive effects of TUBA1B in a pan-carcinoma context. Using data from TCGA, GEO, and other databases, we analyzed TUBA1B expression across various carcinoma types using transcriptional profiling, prognostic implications, genetic and epigenetic alterations, methylation patterns, and immunological significance. To validate our findings, we conducted Western blot analysis to assess TUBA1B protein levels in matched breast cancer tissue samples and performed CCK-8 proliferation assay, flow cytometry, transwell invasion, and migration assays to comprehensively examine the functional impact of TUBA1B on breast cancer cells. Our pan-cancer analysis found TUBA1B upregulation across most tumor types, with varying expression patterns in distinct immune and molecular subtypes. High TUBA1B expression was an independent risk factor and associated with poor prognoses in several cancers, including BRCA, KICH, LGG, LUAD, and MESO. TUBA1B also demonstrates moderate to high diagnostic accuracy in most tumor types. Increased m6A methylation levels were observed in the TUBA1B gene, while its promoter region displayed low methylation levels. TUBA1B's expression impacted some cancers by elevating tumor mutation burden, microsatellite instability, neoantigen formation, immune cell infiltration, and the modulation of immune checkpoints. Functional enrichment analysis highlights TUBA1B's involvement in important cellular processes such as the cell cycle, p53 signaling, cell senescence, programmed cell death, and the regulation of immune-related pathways. Moreover, our study reveals higher TUBA1B protein expression in breast cancer tissues compared to adjacent tissues. In vitro experiments confirm that TUBA1B deletion reduces breast cancer cell proliferation, invasion, and migration while increasing apoptosis. In conclusion, our study suggests that TUBA1B could potentially serve as a diagnostic marker for predicting cancer immunological profiles and survival outcomes and shed light on the expression and role of TUBA1B in breast cancer, providing a solid foundation for considering it as a promising therapeutic target for breast cancer patient treatment.

Cancer is a thorny problem which cannot be conquered by mankind at present and recent researchers have put their focus on tumor microenviroment. Neutrophils, the prominent leukocytes in peripheral blood that accumulate in tumours, serves as frontline cells in response to tumour progression owing to the rapid development of micro biotechnology. Hence, targeted therapy with these neutrophils has made targeting treatment a promising field in cancer therapy.

We broadly summarise some studies on the phenotypes and functions of tumour-associated neutrophils as well as the unique web-like products of neutrophils that play a role in cancer progression-neutrophil extracellular traps-and the interactions between neutrophils and the tumour microenvironment. Moreover, several targeted neutrophils therapeutic studies have made some progress and provided potential strategies for the treatment of cancer.

This review aims to offer a holistic perspective on therapeutic interventions targeting neutrophils to further inspire more researches on cancer therapies.

DNA methylation is a pivotal epigenetic modification that affects gene expression. Tumor immune microenvironment (TIME) comprises diverse immune cells and stromal components, creating a complex landscape that can either promote or inhibit tumor progression. In the TIME, DNA methylation has been shown to play a critical role in influencing immune cell function and tumor immune evasion. DNA methylation regulates immune cell differentiation, immune responses, and TIME composition Targeting DNA methylation in TIME offers various potential avenues for enhancing immune cytotoxicity and reducing immunosuppression. Recent studies have demonstrated that modification of DNA methylation patterns can promote immune cell infiltration and function. However, challenges persist in understanding the precise mechanisms underlying DNA methylation in the TIME, developing selective epigenetic therapies, and effectively integrating these therapies with other antitumor strategies. In conclusion, DNA methylation of both tumor cells and immune cells interacts with the TIME, and thus affects clinical efficacy. The regulation of DNA methylation within the TIME holds significant promise for the advancement of tumor immunotherapy. Addressing these challenges is crucial for harnessing the full potential of epigenetic interventions to enhance antitumor immune responses and improve patient outcomes.

Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.

Cancer accounts for the highest rates of morbidity and mortality worldwide. RNA binding motif protein X-linked (RBMX) is a nuclear RNA-binding protein, associated with certain types of cancer by participating in the integration of sister chromatids and a combination of ribonucleoprotein complexes. However, the specific role of RBMX in cancer immunity remains unknown. This study presents the aberrant expression levels, single-cell distributions, effective prognostic roles, immune cell infiltration associations, and immunotherapy responses of RBMX as a biomarker in various types of cancer. Moreover, it validates the aberrant expression of RBMX in clinical cancer samples. Furthermore, we also evaluated the relationships between RBMX expression and myeloid-derived suppressor cells in clinical samples by immunofluorescent staining. The results showed that knockdown of RBMX can impair the proliferation, migration, and invasion of liver cancer cells. Finally, we indicated that RBMX may play an immunoregulatory role in cancer progression, affecting the therapeutic effects of immune checkpoint inhibitors in patients with cancer.