Kidney Renal Clear Cell Carcinoma (KIRC) is a prevalent urinary malignancies worldwide. Glycosylation is a key post-translational modification that is essential in cancer progression. However, its relationship with prognosis, tumour microenvironment (TME), and treatment response in KIRC remains unclear.

Expression profiles and clinical data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering, Cox regression, and LASSO regression analyses were conducted to develop an optimal glycogene-related signature. The prognostic relevance of this molecular signature was rigorously analyzed, along with its connections to tumour microenvironment (TME), tumour mutation burden, immune checkpoint activity, cancer-immunity cycle regulation, immunomodulatory gene expression patterns, and therapeutic response profiles. Validation was performed using real-world clinical specimens, quantitative PCR (qPCR), and immunohistochemistry (IHC), supported by cohort analyses from the Human Protein Atlas (HPA) database.

A glycogene-associated prognostic scoring system was established to categorize patients into risk-stratified subgroups. Patients in the high-risk cohort exhibited significantly poorer survival outcomes (p < 0.001). By incorporating clinicopathological variables into this framework, we established a predictive nomogram demonstrating strong calibration and a concordance index (C-index) of 0.78. The high-risk subgroup displayed elevated immune infiltration scores (p < 0.001), upregulated expression of immune checkpoint-related genes (p < 0.05), and an increased frequency of somatic mutations (p = 0.043). The risk score positively correlated with cancer-immunity cycle activation and immunotherapy-related signals. The high-risk groups also showed associations with T cell exhaustion, immune-activating genes, chemokines, and receptors. Drug sensitivity analysis revealed that low-risk patients were more sensitive to sorafenib, pazopanib, and erlotinib, whereas high-risk individuals responded better to temsirolimus (p < 0.01). qPCR and IHC analyses consistently revealed distinct expression patterns of MX2 and other key genes across the risk groups, further corroborated by the HPA findings.

This glycogene-based signature provides a robust tool for predicting prognosis, TME characteristics, and therapeutic responses in KIRC, offering potential clinical utility in patient management.

Cancer remains a significant threat to human health due to its multifaceted causes and complex pathogenesis. While advancements in research have improved outcomes for many cancer patients, treatments for specific tumor types still face limitations. Dihydroartemisinin (DHA), an active metabolite of artemisinin and its derivatives, has proven to be an effective anti-malarial agent. Recently, its anticancer potential has garnered increasing interest as it acts through multiple molecular pathways, including anti-proliferation, induction of apoptosis, autophagy and endoplasmic reticulum (ER) stress, anti-metastasis, inhibition of angiogenesis, and modulation of immune function. This review aims to thoroughly explain and summarize the mechanisms of DHA against cancer and the latest progress in this field. Due to the insufficiency of monotherapy in effectively treating cancer, the use of chemotherapy in combination with alternative therapies has witnessed a notable increase in popularity. DHA has shown synergistic anti-tumor efficacy with a range of therapeutic drugs, but its co-delivery with chemotherapeutics has been limited by low solubility and bioavailability. Nanotechnology-assisted co-delivery of anti-tumor agents, utilizing advanced stimulus-triggered drug release systems in tumor cells, offers the potential to enhance selective delivery and increase antitumor efficacy. Additionally, this article provides suggestions for further research on the anticancer effects of DHA.

Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.

A substantial proportion of patients diagnosed with rheumatologic and musculoskeletal diseases (RMDs) exhibit resistance to conventional therapies or experience recurrent symptoms. These diseases, which include autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, are marked by the presence of autoreactive B cells that play a critical role in their pathogenesis. The persistence of these autoreactive B cells within lymphatic organs and inflamed tissues impairs the effectiveness of B-cell-depleting monoclonal antibodies like rituximab. A promising therapeutic approach involves using T cells genetically engineered to express chimeric antigen receptors (CARs) that target specific antigens. This strategy has demonstrated efficacy in treating B-cell malignancies by achieving long-term depletion of malignant and normal B cells. Preliminary data from patients with RMDs, particularly those with lupus erythematosus and dermatomyositis, suggest that CAR T-cells targeting CD19 can induce rapid and sustained depletion of circulating B cells, leading to complete clinical and serological responses in cases that were previously unresponsive to conventional therapies. This review will provide an overview of the current state of preclinical and clinical studies on the use of CAR T-cells and other cellular therapies for RMDs. Additionally, it will explore potential future applications of these innovative treatment modalities for managing patients with refractory and recurrent manifestations of these diseases.

Previous studies suggest the percentage of CD4⁺CD25⁺CD127low regulatory T cells (Tregs) in peripheral blood of patients with hepatocellular carcinoma (HCC) was significantly higher than that in healthy, which may be a significant predictor of HCC clinical outcome, and we examined the utility of Tregs in predicting prognosis in HCC after curative hepatectomy.

77 diagnosed HCC patients from August 2018 to March 2023 were selected as research objects, we retrospectively analyzed whether the preoperative percentage of CD4⁺CD25⁺CD127low Tregs in peripheral blood predicts prognosis after curative hepatectomy in HCC patients. The percentage of CD4⁺CD25⁺CD127low Tregs was detected by flow cytometry.

The percentage of CD4⁺CD25⁺CD127low Tregs was significantly elevated in patients who developed recurrence and death (p < 0.050). X-tile software was used to calculate optimal cut-off value of Treg percentage (5.85%), and patients were divided into two groups with high and low Treg percentage. Patients with higher preoperative Treg percentage had a significantly poorer prognosis (p < 0.050). Cox regression demonstrated the percentage of CD4⁺CD25⁺CD127low Tregs was an independent indicator for poor prognosis after hepatectomy. The Recurrence-free survival (RFS) (the log-rank test, p < 0.001) and Overall survival (OS) (the log-rank test, p = 0.008) in patients with higher Treg percentage were significantly lower than that in patients with lower Treg percentage. The results were confirmed by the subgroup analysis.

The percentage of CD4⁺CD25⁺ CD127low Tregs in peripheral blood is associated with poor prognosis in HCC patients. It can be suggested as a potential prognostic indicator for HCC patients after hepatectomy and complement existing risk stratification tools. Measuring the percentage of CD4⁺CD25⁺ CD127low Tregs may contribute to the formulation of treatment strategies and the improvement of the prognosis for HCC patients.

With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.

NSD2 has been implicated in the pathogenesis of multiple cancers, exhibiting mutations or overexpression that contribute to tumor progression and poor clinical outcomes. In Mantle Cell Lymphoma (MCL), approximately 15% of patients harbor NSD2 mutations; however, its clinical significance remains to be fully elucidated. In our study, we analyzed Next Generation Sequencing (NGS) data from 147 MCL patients and identified NSD2 mutations in 8.84% (13/147) of cases, with 92.31% (12/13) demonstrating bone marrow involvement. Immunohistochemical (IHC) evaluation of NSD2 protein expression in 39 patients revealed that high levels of NSD2 protein expression were associated with higher Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, poorer treatment response, inferior overall survival (OS) and progression-free survival (PFS). Furthermore, NSD2 expression is strongly associated with aggressive histologic variants, including elevated c-MYC protein expression and a high Ki-67 proliferation index. Our analysis of the cBioPortal database, encompassing lymphoma patients, uncovered that NSD2 mutations are most prevalent in MCL. Specifically, E1099K and T1150A point mutations were linked to poorer prognoses. Additionally, our examination of the Gene Expression Omnibus (GEO) database (GSE93291) revealed a correlation between NSD2 mRNA expression levels and MKI67, with elevated NSD2 mRNA expression being associated with reduced survival rates. Tumor-infiltrating Immune Cell Analysis with CIBERSORT in GSE93291 revealed the correlation with increased intratumoral regulatory T cells (Tregs). According to our research, NSD2 mutations exhibit extremely aggressive biological behavior, and a worse prognosis is associated with higher levels of NSD2 in both mRNA and protein expression. We believe that NSD2 stands as a valuable prognostic marker and a potential therapeutic target in MCL.

In recent years, a growing body of evidence has suggested a correlation between Hashimoto's thyroiditis (HT) and the onset and progression of papillary thyroid carcinoma (PTC). However, the mechanism underlying the relationship between HT and PTC remains incompletely understood. This review discusses the literature on the correlation between PTC and HT and summarizes the research concerning the immunological interplay between these two conditions. It also delves into tumor-associated cells (such as CD8+ T cells), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs), alongside other tumor-associated factors, including interleukins (ILs), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor-1 (HIF-1), highlighting their roles in the interaction between PTC and HT. We also explore the strategic direction of immunotherapy in thyroid malignancies, particularly PTC with HT, and propose novel targeted immunotherapies for advanced thyroid cancer.

Regulatory T cells can suppress activated T-cell proliferation by direct cell contact, although the exact mechanism is poorly understood. Identification of a Treg-specific cell surface molecule that mediates suppression would offer a unique target for cancer immunotherapy to inhibit Treg immunosuppressive function or deplete Tregs in the tumor microenvironment. In this study, we explored a method of whole-cell immunization using a Treg-like cell line (MoT cells) to generate and screen monoclonal antibodies that bound cell surface proteins in their native conformations and functionally reversed Treg-mediated suppression. From the 105 hybridomas that bound to the MoT cell surface, a functional screen utilizing conventional Treg suppression assays revealed 32 candidate antibodies that exhibited functional activity (reversed or enhanced suppressive activity). As an example, we characterized 1 anti-MoT mAb, 12E7, that exhibited strong binding to MoT cells and conventional Treg cell surfaces. This candidate antibody was subsequently found to bind to a potential suppressive target, CD44, and demonstrated the ability to partially reverse MoT and conventional human Treg-mediated suppression.

This paper discussed the role of AlkB homologue 5 (Alkbh5) in the progression of lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS-induced ALI models were established in Alkbh5 knockout (KO) and knock-in (KI) mice. The m6A levels in lung tissues were analysed using m6A dot assays. The lung injury was analysed by determining ALI-related markers and histological staining. Mouse MLE12 cells were exposed to LPS for in vitro experiments, and the influence of Alkbh5 on cell viability, apoptosis and reactive oxygen species (ROS) production was analysed. RNA-seq analysis was performed to analyse gene changes upon Alkbh5 deficiency. Functions of the Alkbh5-C-C motif chemokine ligand 1 (Ccl1) cascade in ALI were further verified using the Alkbh5 antagonist DDO-2728 and a recombinant protein of Ccl1 (mCcl1). Alkbh5 was upregulated in lung tissues following LPS exposure. Alkbh5 knockout in mice mitigated LPS-induced lung injury, as indicated by reduced serum levels of lung injury markers and reduced immune cell infiltration, fibrosis and apoptosis. Conversely, Alkbh5 overexpression in mice resulted in reverse trends. In vitro, Alkbh5 knockdown in MLE12 cells enhanced cell viability while reducing cell apoptosis and ROS production. Mechanistically, Alkbh5 was found to bind to and destabilise Ccl1 mRNA, leading to increased Treg recruitment. Treatment with DDO-2728 or mCcl1 in mice increased Treg infiltration, thus improving lung tissue pathology and reducing lung injury. This study suggests that Alkbh5 is implicated in ALI progression by reducing Ccl1-mediated Treg recruitment, making it a promising target for ALI management.

As a newly discovered histone modification, abnormal lactation has been found to be present in and contribute to the development of various cancers. The aim of this study was to investigate the potential role between lactylation and the prognosis of breast cancer patients. Lactylation-associated subtypes were obtained by unsupervised consensus clustering analysis. Lactylation-related gene signature (LRS) was constructed by 15 machine learning algorithms, and the relationship between LRS and tumor microenvironment (TME) as well as drug sensitivity was analyzed. In addition, the expression of genes in the LRS in different cells was explored by single-cell analysis and spatial transcriptome. The expression levels of genes in LRS in clinical tissues were verified by RT-PCR. Finally, the potential small-molecule compounds were analyzed by CMap, and the molecular docking model of proteins and small-molecule compounds was constructed. LRS was composed of 6 key genes (SHCBP1, SIM2, VGF, GABRQ, SUSD3, and CLIC6). BC patients in the high LRS group had a poorer prognosis and had a TME that promoted tumor progression. Single-cell analysis and spatial transcriptome revealed differential expression of the key genes in different cells. The results of PCR showed that SHCBP1, SIM2, VGF, GABRQ, and SUSD3 were up-regulated in the cancer tissues, whereas CLIC6 was down-regulated in the cancer tissues. Arachidonyltrifluoromethane, AH-6809, W-13, and clofibrate can be used as potential target drugs for SHCBP1, VGF, GABRQ, and SUSD3, respectively. The gene signature we constructed can well predict the prognosis as well as the treatment response of BC patients. In addition, our predicted small-molecule complexes provide an important reference for personalized treatment of breast cancer patients.

In situ vaccination (ISV) has emerged as a promising strategy in cancer immunotherapy, offering a targeted approach that uses the tumor microenvironment (TME) to stimulate an immune response directly at the tumor site. This method minimizes systemic exposure while maintaining therapeutic efficacy and enhancing safety. Recent advances in nanotechnology have enabled new approaches to ISV by utilizing nanomaterials with unique properties, including enhanced permeability, retention, and controlled drug release. ISV employing nanomaterials can induce immunogenic cell death and reverse the immunosuppressive and hypoxic TME, thereby converting a "cold" tumor into a "hot" tumor and facilitating a more robust immune response. This review examines the mechanisms through which nanomaterials-based ISV enhances anti-tumor immunity, summarizes clinical applications of these strategies, and evaluates its capacity to serve as a neoadjuvant therapy for eliminating micrometastases in early-stage cancer patients. Challenges associated with the clinical translation of nanomaterials-based ISV, including nanomaterial metabolism, optimization of treatment protocols, and integration with other therapies such as radiotherapy, chemotherapy, and photothermal therapy, are also discussed. Advances in nanotechnology and immunotherapy continue to expand the possible applications of ISV, potentially leading to improved outcomes across a broad range of cancer types.

The tumor-immune response is mobilized to suppress tumorigenesis, while the immune microenvironment and lymph node microenvironment are formed gradually during tumor progression. In fact, tumor surface antigens are not easily recognized by antigen-presenting cells. So it is hard for the immune system to kill the newly formed tumor cells effectively. In a normal immune environment, immune function is always suppressed to maintain the stability of the body, and regulatory T cells play an important role in maintaining immune suppression. However, during tumorigenesis, the suppression of regulatory T cell immune functions is more likely to contribute to tumor cell proliferation and migration leading directly to tumor progression. Therefore, focusing on the role of regulatory T cells in tumor immunity could improve tumor immunotherapy outcomes in the clinic. Regulatory T cells are more mature in hematologic system tumors than in solid tumors. However, there are continuing efforts to apply regulatory T cells for immunotherapy in solid tumors. This review describes the role of regulatory T cells in solid tumor immunotherapy from the perspective of prognosis, immune microenvironment remodeling, and current clinical applications. This summary could help us better understand the mechanisms of regulatory T cells in solid tumor immunotherapy and further expand their clinical application.

Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.

Regulatory T cells (Tregs) are the main immunosuppressive cells in tumor immune microenvironment (TIME). However, systemic Treg depletion is not favored due to the crucial role of Tregs in the maintenance of immune homeostasis and prevention of autoimmunity. Recently, CCR8 has been identified as a key chemokine receptor expressed on tumor-infiltrating Tregs and targeted blockade of CCR8 exerts anticancer effect in several cancer types, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear.

We determined the involvement of CCR8+ Tregs in HCC using human HCC tissues and TCGA database, and examined the anticancer effect and the underlying molecular mechanisms of the CCR8 antagonist, IPG0521m, which was developed in house, in murine liver cancer model with flow cytometry, bulk and single-cell RNA sequencing and Real-Time PCR.

Remarkable increase in CCR8+ Tregs was observed in human HCC tissues. Treatment of syngeneic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8+ T cells in tumor tissues. Bulk RNA sequencing analysis indicated that IPG0521m treatment resulted in remarkable increase in antitumor immunity. Furthermore, single-cell RNA sequencing analysis demonstrated that IPG0521m treatment resulted in a switch of Tregs from high immunosuppression to low immunosuppression phenotype, associated with elevated CD8+ T and NK cell proliferation and cytotoxicity, and decreased myeloid-derived suppressor cells and tumor-associated macrophages in the tumor tissues.

IPG0521m inhibited liver cancer growth via reducing the immunosuppressive function of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancers.

Cutaneous melanoma is a common cancer in Australia and New Zealand, Europe, and North America, and its incidence is still increasing in many regions. Ultraviolet (UV) radiation exposure (for example, through excessive sunlight exposure) remains the primary risk factor for melanoma; however, public awareness campaigns have led to a marked reduction in mortality. In addition to genetic damage from UV radiation, specific genetic alterations have been linked to melanoma. The stage of the tumour at the time of diagnosis is of greater importance for melanoma prognosis than in almost any other cancer. Context-dependent genetic mutations that attenuate tumour-suppressive mechanisms or activate growth-promoting signalling pathways are crucial factors in the development of cutaneous melanoma. In addition to external factors such as UV radiation, the tumour microenvironment can contribute to melanoma progression, invasion and metastasis. Cutaneous melanoma treatment has improved considerably over the past decade with the discovery and development of immune checkpoint inhibitors and therapy targeting BRAF and MEK. Over the next decade, several priorities are likely to influence melanoma research and management, including the continued advance of precision medicine methods to identify the most suitable patients for the most effective treatment, with the aim of improving clinical outcomes.

Effector regulatory T cells expressing C-C chemokine receptor 4 (CCR4) suppress antitumor immune responses. We conducted a phase I clinical trial to evaluate the safety and efficacy of preoperative combination therapy with mogamulizumab (an anti-CCR4 antibody) and nivolumab (an anti-programmed death-1 antibody) in patients with solid tumors.

Patients with operable solid tumors were enrolled in a 3+3 design, with preoperative nivolumab (3.0 mg/kg) administered intravenously every 2 weeks three times and mogamulizumab at 0.1 mg/kg (cohort 1), 0.3 mg/kg (cohort 2), or 1.0 mg/kg (cohort 3) every week four times. The primary endpoints were safety and the effects of depleting Forkhead box P3+ (FoxP3+) T cells in the tumor.

16 patients were enrolled between June 2016 and April 2020, including those with renal (n=7), lung (n=5), esophageal (n=3), and oral (n=1) cancers. Grade 3-4 treatment-related adverse events were observed in 6 of 16 patients, with lymphopenia (25%) and maculopapular rash (13%) being the most frequent. Grade 5 interstitial pneumonia was observed in one patient; however, the cause of death was disease progression. There were three partial responses (PRs) (one lung and two esophageal cancers) among clinical responses and one complete response (one lung cancer) and nine PRs (five kidney, two lung, and two esophageal cancers) among pathological responses. CCR4+FoxP3+ T cells were depleted in the tumors of all patients and increases in lymphocytes in tumor tissue according to the tumor immune microenvironment classification were observed in 50% of the patients, which correlated with a better prognosis.

The preoperative combination of mogamulizumab and nivolumab was safely managed, exerted antitumor effects, and may be an effective option in the preoperative setting.

The present study was registered with ClinicalTrials.gov as NCT02946671 (registration date 2016-10-05).

To date, many types of immune cells have been identified, but their precise role in cancer immunity remains unclear. Understanding the immune responses involved in cancer and the cancer microenvironment is becoming increasingly important for elucidating disease mechanisms. In recent years, the application of intravital imaging in cancer research has provided new insights into the mechanisms of cancer-specific immune events, including innate and adaptive immunity.

In this review, we focus on the emerging role of intravital imaging in cancer research and describe how cancer and immune cells can be observed using intravital imaging in vivo. We also discuss new insights gained by this state-of-the-art technique.

Intravital imaging is a relatively new field of research that offers significant advantages, including the ability to directly capture cell-cell interactions, pathophysiology, and immune cell dynamics in the cancer microenvironment in vivo.

Breast cancer is a leading cause of morbidity and mortality in women, and its progression is closely linked to the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), key components of the TME, play a crucial role in promoting tumor growth by driving cancer cell proliferation, invasion, extracellular matrix (ECM) remodeling, inflammation, chemoresistance, and immunosuppression. CAFs exhibit considerable heterogeneity and are classified into subgroups based on different combinations of biomarkers. Single-cell RNA sequencing (scRNA-seq) enables high-throughput and high-resolution analysis of individual cells. Relying on this technology, it is possible to cluster complex CAFs according to different biomarkers to analyze the specific phenotypes and functions of different subpopulations. This review explores CAF clusters in breast cancer and their associated biomarkers, highlighting their roles in disease progression and potential for targeted therapies.

Regulatory T (Treg) cells have a central role in the maintenance of immune surveillance and tolerance. They can migrate from lymphoid organs to blood and then into tissues and egress from tissues into draining lymph nodes. Specialized endothelial cells of blood and lymphatic vessels are the key gatekeepers for these processes. Treg cells that transmigrate across single-cell layers of endothelial cells engage in bidirectional crosstalk with these cells and regulate vascular permeability by promoting structural modifications of blood and lymphatic endothelial cells. In turn, blood and lymphatic endothelial cells can modulate Treg cell recirculation and residency. Here, we discuss recent insights into the cellular and molecular mechanisms of the crosstalk between Treg cells and endothelial cells and explore potential therapeutic strategies to target these interactions in autoimmunity, transplantation and cancer.

As immunosuppressive cells, Regulatory T cells (Tregs) exert their influence on tumor immune escape within the tumor microenvironment (TME) by effectively suppressing the activity of other immune cells, thereby significantly impeding the anti-tumor immune response. In recent years, the metabolic characteristics of Tregs have become a focus of research, especially the important role of lipid metabolism in maintaining the function of Tregs. Consequently, targeted interventions aimed at modulating lipid metabolism in Tregs have been recognized as an innovative and promising approach to enhance the effectiveness of tumor immunotherapy. This review presents a comprehensive overview of the pivotal role of lipid metabolism in regulating the function of Tregs, with a specific focus on targeting Tregs lipid metabolism as an innovative approach to augment anti-tumor immune responses. Furthermore, we discuss potential opportunities and challenges associated with this strategy, aiming to provide novel insights for enhancing the efficacy of cancer immunotherapy.

Lung squamous cell carcinoma (LUSC), accounting for 30% of lung cancer cases, lacks adequate research due to limited understanding of its molecular abnormalities. Our study analyzed public LUSC datasets to explore the tumor microenvironment (TME) composition using scRNA-seq from two cohorts. Applying non-negative matrix factorization, we identified unique malignant cell phenotypes, or meta-programs (MPs), based on gene expression patterns. Survival analysis revealed the clinical relevance of these MPs. Findings illuminated a TME landscape enriched with immune cells-CD8 + T, exhausted T, CD4 + T, and naive T cells-and suggested roles for myeloid cells, like cDC1 and pDCs, in LUSC progression. Different MPs highlighted the heterogeneity of malignant cells and their clinical implications. Targeting MP-specific genes may enable personalized therapy, especially for early-stage LUSC. This study offers insights into immune cell function in tumor dynamics, identifies MPs, and paves the way for novel LUSC strategies, enhancing early intervention, personalized treatment, and prognosis, ultimately improving patient outcomes.

Inflammatory bowel disease (IBD) is a relapsing disorder characterized by uncontrolled chronic inflammation of the gastrointestinal tract, posing a significant therapeutic challenge owing to the limited efficacy and undesirable side effects of current therapeutic options. A key pathological hallmark of IBD is the excessive production of reactive oxygen species (ROS). Hence, therapeutic strategies aimed at reducing ROS levels are promising for relieving these inflammatory conditions. Vitamin C-a natural nutrient for the human body-is well known for its potent antioxidant effects. However, the clinical development of vitamin C as a therapeutic drug has been hindered by its poor stability, rapid metabolism, and inadequate tissue accumulation. Herein, we report that the bioavailability of vitamin C can be enhanced by chemically reprogramming it with a small panel of long-chain fatty acids that aid in the aqueous self-assembly of the resulting drug conjugates to create self-deliverable nanoassemblies, enhancing their inflammation disease-oriented delivery and cellular uptake. In mice with dextran sulfate sodium-induced colitis, the optimal vitamin C-lipid nanoassemblies preferentially accumulated in inflamed colonic tissues following systemic administration and substantially ameliorated disease severity. We extended this strategy to incorporate the clinically approved glucocorticoid budesonide into the vitamin C nanosystem, facilitating a synergistic combination. In the chronic colitis model, the combination treatment reduced inflammation without compromising global immunity. Mechanistically, the treatment modulated the intestinal inflammatory microenvironment and altered the immune cell landscape, partly through regulation of the gut microbiome. Given its anticipated negligible side effects, this novel nanoassembly platform leveraging small-molecule lipidation may become a promising therapeutic for treating various inflammatory diseases.

Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.

In the tumor immunosuppressive microenvironment (TIME), regulatory T cells (Tregs) critically suppress anticancer immunity, characterized by high expression of glucocorticoid-induced TNF receptor (GITR) expression and sensitivity to reactive oxygen species (ROS). This study develops a near-infrared (NIR)-responsive hollow nanocomplex (HPDA-OPC/DTA-1) using hollow polydopamine nanoparticles (HPDA), endowed with thermogenic and antioxidative properties, specifically targeting Tregs to activate antitumor immunity. The GITR agonist DTA-1, combined with the antioxidant oligomeric proanthocyanidins (OPC) to deplete Tregs. However, Tregs depletion alone may not sufficiently trigger robust immune responses. The HPDA nanocarrier enhances thermogenic and antioxidative capacities, supporting photothermal immunotherapy. The HPDA-OPC/DTA-1 demonstrates NIR responsiveness for both photothermal therapy (PTT) and OPC release, while facilitating Tregs depletion via DTA-1 and reducing ROS levels, thereby reviving antitumor immunity. Notably, intratumoral CD4+CD25+FOXP3+ Tregs exhibited a 4.08-fold reduction alongside a 49.11-fold increase in CD8+ T cells/Tregs relative to controls. Enhanced dendritic cells (DCs) maturation and immunogenic cell death (ICD) induction further demonstrate that HPDA-OPC/DTA-1 alleviates immunosuppression and activates antitumor immunity. Ultimately, the observed tumor inhibitory effect (tumor volume: 6.75-fold versus the control) and an over 80% survival rate highlight the therapeutic potential of combining Tregs targeting, antioxidant strategy, and photothermal immunotherapy for effective cancer treatment.

Embryo implantation in the mare occurs just over one month after fertilization, coinciding with the production of chorionic gonadotropin. The factors that regulate this late implantation in the mare, and whether they are unique to horses or shared with more invasive embryo implantation in other species, remain poorly understood. This study aimed to determine and compare the transcriptome and subpopulations of endometrial cells before and after embryo implantation in the horse. Single-cell RNA sequencing was used to characterize the transcriptome of nearly 97,000 endometrial cells collected from biopsies of the endometrium at the beginning (day 33 of gestation) and after embryo implantation (day 42 of gestation) in mares. Sixteen immune and 24 non-immune cell clusters were identified, representing known major cell populations as well as novel subpopulations of horse immune cells such as resident innate lymphoid cells and mucosal-associated invariant T cells. Contrary to current knowledge, endometrial natural killer (eNK) cells were the most abundant endometrial leukocyte population during implantation in horses. Moreover, eNK cells not only expressed genes that may interact with fetal MHC I, such as LY49F, but also exert immunoregulatory functions independent of MHC I expression, such as CD96/TIGIT. Analogous to other species studied, upregulation of CXCR4 was found in several subpopulations of immune cells. Our results suggest that despite distinctive and later placentation compared with humans, horses share some key similarities in the mechanisms of embryo implantation.

Regulatory T cells (Tregs) play an important role in the immune system through the regulation of immunological self-tolerance and homeostasis. Furthermore, increasing evidence suggests the potential contribution of Tregs beyond immunity in the process of repairing various injured tissues. Tregs are generally characterised by the constitutive expression of forkhead box protein 3 (FOXP3) transcription factor in the nucleus and high expression levels of CD25 and CTLA-4 on the cell surface. To date, a large number of molecules have been identified as key regulators of Treg differentiation and function. Among these molecules are prostanoids, which are multifaceted lipid mediators. Prostanoids are produced from arachidonic acid through the catalytic activity of the enzyme cyclooxygenase and exert their functions through the 9 cognate receptors, DP1-2, EP1-EP4, FP, IP and TP. We briefly review previous studies on the regulatory mechanism of Tregs and then discuss recent works on the modulatory role of prostanoids.

Accumulation of regulatory T (Treg) cells, an immunosuppressive population, limits the efficacy of immunotherapy in NSCLC. C-C motif chemokine receptor 8 (CCR8) is selectively expressed in tumor-infiltrating Treg cells and is, therefore, considered an ideal target.

The efficacy and safety of anti-CCR8 monotherapy and its combination with programmed cell death protein-1 (PD1) inhibitor were evaluated in four NSCLC-bearing mice models. To track the dynamic changes in tumor microenvironment, we performed the single-cell RNA sequencing, the single-cell T-cell receptor sequencing analysis, the flow cytometry, the multi-color immunofluorescence, and the Luminex assay on tumors after three, seven, 14, and 21 days of different treatment regimens. Then, in vitro and in vivo experiments were applied to validate our findings and explore molecular mechanisms of the synergistic effects.

Across four NSCLC-bearing mice models, the combination of CCR8 antibody and PD1 inhibitor significantly reduced tumor growth (p < 0.05) without obvious mouse body weight drops and systemic cytokine storm. The anti-CCR8 therapy synergizes with PD1 blockade by remodeling the tumor microenvironment and disrupting CCR8+Treg-C-C motif chemokine ligand 5 (CCL5)+ dendritic cells (DC) interaction. Mechanistically, therapeutic depletion of CCR8+Treg cells combined with PD1 inhibitor extremely increased interleukin-12 secretion by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway activation on CCL5+ DCs, thereby promoting cytotoxic activity of CD8+ T cells. The therapeutic potential of the CCR8 antibody LM-108 in combination with immunotherapy was observed in clinical patients with advanced NSCLC.

Overall, CCR8 expression on tumor-infiltrating Treg cells is correlated with immunosuppressive function on DCs and CD8+ T cells, thus impeding antitumor immunity.

Targeting the dysregulation of epigenetic mechanisms in cancer has emerged as a promising therapeutic strategy. Although the significant rationale progress of epigenetic therapies in blocking cancer cells, how epigenetic regulation shapes tumor microenvironment (TME) and establishes antitumor immunity remains less understood. Recent study focus has been put on the epigenetic-mediated changes in the fate of immune cells, including the differentiation, expansion, recruitment, functionalization, and exhaustion of T cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and B cells within the TME. Here, we review the latest molecular and clinical insights into how DNA modifications, histone modification, and epitranscriptome-related regulations shape immune cells of various cancers. We also discuss opportunities for leveraging epigenetic therapies to improve cancer immunotherapies. This review provides the epigenetic foundations of cancer immunity and proposes the future direction of combination therapies.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor-promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor-promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor-suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor-promoting and tumor-suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.

Prostate cancer is one of the most common malignancies in men. The tumour microenvironment (TME) has a critical role in the initiation, progression, and metastasis of prostate cancer. TME contains various cell types, including cancer-associated fibroblasts (CAFs), endothelial cells, immune cells such as macrophages, lymphocytes B and T, natural killer (NK) cells, and other proteins such as extracellular matrix (ECM) components. The interactions and communications between these cells within the TME are crucial for the growth and response of various solid tumours, such as prostate cancer to different anticancer modalities. In this review article, we exemplify the various mechanisms by which the TME influences prostate cancer progression. The roles of different cells, cytokines, chemokines, and growth factors in modulating the immune response and prostate tumour growth will be discussed. The impact of these cells and factors and other ECM components on tumour cell invasion and metastasis will also be discussed. We explain how these interactions in TME can affect the response of prostate cancer to therapy. We also highlight the importance of understanding these interactions to develop novel therapeutic approaches for prostate cancer.

Lymphoid leukemias represent a significant global health burden, leading to substantial morbidity and mortality. The intricate interplay between leukemic cells and their surrounding tumor microenvironment (TME) is pivotal in disease initiation, progression, and therapeutic resistance. Comprising a dynamic milieu of stromal, immune, and leukemic cell populations, the TME orchestrates a complex network of signaling pathways and molecular interactions that foster leukemic cell survival and proliferation while evading immune surveillance. The crosstalk between these diverse cellular components within the TME not only fuels tumor progression but also confers resistance to conventional therapies, including the development of multi-drug resistance (MDR). Recognizing the pivotal role of the TME in shaping disease outcomes, novel therapeutic approaches targeting this dynamic ecosystem have emerged as promising strategies to complement existing anti-leukemic treatments. As a result, drugs that target the TME have been developed as complementary strategies to those that directly attack tumor cells. Thus, a detailed understanding of the TME components and their interactions with tumor cells is critical. Such knowledge can guide the design and implementation of novel targeted therapies for lymphoid leukemias.

Radiotherapy is a cornerstone of lung cancer management, though its efficacy is frequently undermined by intrinsic and acquired radioresistance. This review examines the complexity of lung tumors, highlighting their potential as a reservoir of novel targets for radiosensitization. Ionizing radiation (IR) primarily exerts its effects through oxidative damage and DNA double-strand breaks (DSBs). Lung cancer cells, however, develop mutations that enhance DNA damage response (DDR) and suppress cell death pathways. Additionally, interactions between tumor cells and tumor microenvironment (TME) components-including immune cells, stromal cells, and molecular mediators such as cytokines, chemokines, and growth factors-contribute to resistance against IR. Understanding these intricate relationships reveals potential targets to improve radiotherapy outcomes. Promising targets include DDR pathways, immunosuppressive cells and molecules, hypoxia, proangiogenic mediators, and other key signaling pathways. This review discusses emerging strategies, such as combining radiotherapy with immunomodulators, hypoxia and proangiogenic inhibitors, DDR-targeting agents, and other innovative approaches. By offering a comprehensive analysis of the lung TME, this review underscores opportunities to enhance radiotherapy effectiveness through targeted radiosensitization strategies.

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain malignancies in adults. Standard approaches, including surgical resection followed by adjuvant radio- and chemotherapy with temozolomide (TMZ), provide only transient control, as GBM frequently recurs due to its infiltrative nature and the presence of therapy-resistant subpopulations such as glioma stem cells (GSCs). GSCs, with their quiescent state and robust resistance mechanisms, evade conventional therapies, contributing significantly to relapse. Consequently, current treatment methods for GBM face significant limitations in effectively targeting GSCs. In this review, we emphasize the relationship between GBM recurrence and GSCs, discuss the current limitations, and provide future perspectives to overwhelm the challenges associated with targeting GSCs. Eliminating GSCs may suppress recurrence, achieve durable responses, and improve therapeutic outcomes for patients with GBM.

Reprogramming of the tumor microenvironment (TME) plays a critical role in gastric cancer (GC) progression and metastasis. However, the multidimensional features between primary tumors and organ-specific metastases remain poorly understood. In this study, we characterized the dynamic heterogeneity of GC from primary to metastatic stages. We identified seven major cell types and 27 immune and stromal subsets. Immune cells decreased, while immunosuppressive cells increased in ovarian and peritoneal metastases. A 30-gene signature for ovarian metastasis was validated in GC cohorts. Additionally, critical ligand-receptor interactions, including LGALS9-MET in liver metastasis and PVR-TIGIT in lymph node metastasis, were identified as potential therapeutic targets. Furthermore, CLOCK, a transcription factor, was associated with poor prognosis and influenced immune cell interactions and migration. Collectively, this study provides valuable insights into TME dynamics in GC and highlights potential avenues for targeted therapies.

Regulatory T cells (Tregs) are a suppressive CD4+ T cell population that limit the antitumor immune response. In this study, we analyzed the chromatin accessibility of Tregs in the murine tumor microenvironment (TME) to identify tumor-specific accessible peaks and if these are altered over time in the tumor microenvironment, with or without anti-PD-1 immunotherapy. We found that despite little change in chromatin accessibility of Tregs in the tumor over time, Tregs have a distinct chromatin accessibility signature in the TME compared with Tregs in the periphery. This distinct tumor Treg chromatin accessibility profile highlights reduced accessibility at loci important for an CD4+ conventional T cell (CD4+ Foxp3-) effector phenotype. Analysis of chromatin accessibility in Tregs from B16 and MC38 tumor models indicated that Tregs from skin-resident tumors are most similar to naïve skin resident Tregs but still bear key differences attributable to the TME. We also found that Tregs do not alter their transcriptome or chromatin accessibility following immunotherapy. We conclude that although chromatin accessibility in Tregs is somewhat similar to their tissue residency, the TME may drive a unique chromatin accessibility profile. Treg chromatin accessibility in the tumor appears remarkably stable and unaltered by tumor type, over time, or following immunotherapy.

Enhancing antigen cross-presentation is essential for the development of a tumor neoantigen vaccine. One approach is to stimulate antigen-presenting cells (APCs) to uptake neoantigens. Mycobacterium tuberculosis (MTb) contains pathogen-associated molecular patterns (PAMPs) recognized by APCs and adhesion molecules that facilitate MTb invasion of APCs. Therefore, we suggest using MTb as a carrier to enhance APC phagocytosis of neoantigens, thereby promoting antigen cross-presentation.

The successful preparation of the MTb carrier (phMTb) was confirmed through electron and confocal microscopy. Fluorescence microscopy was used to detect PAMPs and adhesion molecules on phMTb as well as to observe its role in aiding dendritic cells (DCs) in antigen uptake into endosomes or lysosomes. Flow cytometry was used to assess the retention of PAMPs and adhesion molecules on phMTb, investigate antigen uptake by DCs, evaluate their activation and maturation status, examine the presentation of tumor neoantigens, and analyze immune cells in draining lymph nodes and tumor tissues. The efficacy of phMTb vaccine formulations in combination with anti-programmed cell death protein 1 (PD-1) antibody therapy was assessed using the MC38 mouse tumor models. Adverse effects were evaluated through H&E staining of major organs, assessment of reproductive capability and detection of biochemical indices.

The engineered porous hollow phMTb carrier successfully encapsulated model tumor neoantigens, with or without the adjuvant CpG. The phMTb retained PAMPs and adhesion molecules on its surface, similar to the parental MTb, thereby enhancing DC uptake of phMTb and its formulations containing tumor neoantigens and CpG. Vaccines formulated with phMTb facilitated DC maturation, activation, cross-presentation of tumor neoantigens, and promoted migration of phMTb-laden DCs to lymph nodes, enhancing effector and memory CD8+ T lymphocyte function. In murine tumor models, immunization with phMTb-formulated neoantigen vaccines elicited a robust tumor-specific cytotoxic T lymphocyte immune response with minimal adverse effects. Additionally, vaccination with phMTb-formulated neoantigen vaccines effectively reversed the tumor's immune-suppressive microenvironment. Concurrent administration of the PD-1 antibody with the phMTb-formulated neoantigen vaccine exhibited significant synergistic therapeutic effects.

The results of our study highlight the potential clinical translation of personalized tumor neoantigen vaccines using the phMTb carrier.

Regulatory T (Treg) cells, immunosuppressive CD4+ T cells, can impede anti-tumor immunity, complicating cancer treatment. Since their discovery, numerous studies have been dedicated to understand Treg cell biology, with a focus on checkpoint pathways' role in their generation and function. Immune checkpoints, such as PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, and OX40, are pivotal in controlling Treg cell expansion and activity in the tumor microenvironment (TME), affecting their ability to suppress immune responses. This review examines the complex relationship between these checkpoints and Tregs in the TME, and how they influence tumor immunity. We also discuss the therapeutic potential of targeting these checkpoints to enhance anti-tumor immunity, including the use of immune checkpoint blockade (ICB) therapies and novel approaches such as CCR8-targeted therapies. Understanding the interaction between immune checkpoints and Treg cells can lead to more effective immunotherapeutic strategies, such as combining CCR8-targeted therapies with immune checkpoint inhibitors, to improve patient outcomes in cancer treatment.

T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro-inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a two-edged sword; it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).