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A steady dysfunctional state caused by chronic antigen stimulation in the tumor microenvironment (TME) is known as CD8 + T cell exhaustion. Exhausted-like CD8 + T cells (CD8 + Tex) displayed decreased effector and proliferative capabilities, elevated co-inhibitory receptor generation, decreased cytotoxicity, and changes in metabolism and transcription. TME induces T cell exhaustion through long-term antigen stimulation, upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of immunosuppressive cytokines. CD8 + Tex may be both the reflection of cancer progression and the reason for poor cancer control. The successful outcome of the current cancer immunotherapies, which include immune checkpoint blockade and adoptive cell treatment, depends on CD8 + Tex. In this review, we are interested in the intercellular signaling network of immune cells interacting with CD8 + Tex. These findings provide a unique and detailed perspective, which is helpful in changing this completely unpopular state of hypofunction and intensifying the effect of immunotherapy.

Summary Aging is accompanied by altered T-cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T-cell exhaustion and aging-associated immune dysfunction. In this study, we demonstrate that T-cell immunoglobulin mucin domain-3 (Tim-3), another exhaustion marker, is up-regulated on aged T cells, especially CD8+ T cells. Tim-3-expressing cells also produced PD-1, but Tim-3+PD-1+ CD8+ T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim-3-PD-1+ cells. Tim-3+PD-1+ CD8+ T cells showed more evident properties associated with exhaustion than Tim-3-PD-1+ CD8+ T cells: an exhaustion-related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL-10 and induced normal CD8+ T cells to produce IL-10, which might contribute to immune dysregulation in aged mice. The generation of Tim-3-expressing CD8+ T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR V[beta] usage. In conclusion, we found that a CD8+ T-cell population with age-associated exhaustion was distinguishable by its expression of Tim-3. These results provide clues for understanding the alterations that occur in T-cell populations with age and for improving dysfunctions related to the aging of the immune system.

Lung cancer continues to be a major contributor to cancer-related deaths globally. Recent advances in immunotherapy have introduced promising treatments targeting T cell functionality. Central to the efficacy of these therapies is the role of T cells, which are often rendered dysfunctional due to continuous antigenic stimulation in the tumor microenvironment–a condition referred to as T cell exhaustion. This review addresses the critical challenge of T cell exhaustion in non-small cell lung cancer (NSCLC), offering a detailed examination of its molecular underpinnings and the resultant therapeutic ineffectiveness. We synthesize current knowledge on the drivers of T cell exhaustion, evaluate emerging strategies for its reversal, and explore the potential impact of these insights for enhancing the clinical efficacy of immunotherapies. By consolidating reported clinical trials and preclinical studies, this article highlights innovative approaches to modulate immune responses and improve patient outcomes, thus providing a roadmap for future research and therapeutic development in lung cancer immunotherapy.

Background HBV infection is the leading risk factor for HCC. HBV infection has been confirmed to be associated with the exhaustion status of CD8 + T cells and immunotherapeutic efficacy in HCC. In this study, we aimed to investigate the prognostic value of the CD8 + T-cell exhaustion signature and immunotherapy response in patients with HBV-related HCC. Methods We identified different clusters of HBV-related HCC cells by single-cell RNA sequencing (scRNA-seq) and identified CD8 + T-cell exhaustion-related genes (TERGs) by pseudotime analysis. We conducted differential expression analysis and LASSO Cox regression to detect genes and construct a CD8 + T-cell exhaustion index (TEI). We next combined the TEI with other clinicopathological factors to design a prognostic nomogram for HCC patients. We also analysed the difference in the TEI between the non-responder and responder groups during anti-PD-L1 therapy. In addition, we investigated how HBV induces CD8 + T lymphocyte exhaustion through the inhibition of tyrosine metabolism in HCC using gene set enrichment analysis and RT‒qPCR. Results A CD8 + T-cell exhaustion index (TEI) was established with 5 TERGs (EEF1E1, GAGE1, CHORDC1, IKBIP and MAGOH). An AFP level > 500 ng, vascular invasion, histologic grade (G3-G4), advanced TNM stage and poor five-year prognosis were related to a higher TEI score, while HBV infection was related to a lower TEI score. Among those receiving anti-PD-L1 therapy, responders had lower TEIs than non-responders did. The TEI also serves as an independent prognostic factor for HCC, and the nomogram incorporating the TEI, TNM stage, and vascular invasion exhibited excellent predictive value for the prognosis in HCC patients. RT‒qPCR revealed that among the tyrosine metabolism-associated genes, TAT (tyrosine aminotransferase) and HGD (homogentisate 1,2 dioxygenase) were expressed at lower levels in HBV-HCC than in non-HBV HCC. Conclusion Generally, we established a novel TEI model by comprehensively analysing the progression of CD8 + T-cell exhaustion, which shows promise for predicting the clinical prognosis and potential immunotherapeutic efficacy in HBV-related HCC patients.

Background While small extracellular vesicles (sEVs)-derived circular RNAs (circRNAs) have been emerged as significant players in cancer, the function and underlying mechanism of sEVs-derived circRNAs in anti-cancer immunity remain unclear. Methods Gastric cancer (GC)-derived circRNAs were identified using RNA-seq data from GEO datasets and quantitative reverse transcription polymerase chain reaction (qRT-PCR), RNA immunoprecipitation, dual-luciferase assay, and bioinformatics analysis were performed to investigate the regulatory axis. Transwell assay, wound healing assay, cell counting kit-8 (CCK-8) assay, and xenograft models were used to evaluate its role in GC progression in vivo and in vitro. The delivery of specific circRNAs into sEVs were verified through electron microscopy, nanoparticle tracking analysis (NTA) and fuorescence in situ hybridization (FISH). Flow cytometric analysis and immunohistochemical staining were conducted to find out how specific circRNAs mediated CD8 +  T cell exhaustion and resistant to anti-programmed cell death 1 (PD-1) therapy. Results We identified that circ_0001947, packaged by GC-derived sEVs, was obviously elevated in GC and was associated with poor clinical outcome. High circ0001947 level augmented the proliferation, migration, and invasion of GC cells. Mechanistically, circ0001947 sponged miR−661 and miR−671−5p to promote the expression of CD39, which further facilitated CD8 +  T cell exhaustion and immune resistance. Conversely, blocking circ_0001947 attenuated CD8 +  T cell exhaustion and increased the response to anti-PD−1 therapy. Conclusions Our study manifested the therapeutic potential of targeting sEVs-transmitted circ_0001947 to prohibit CD8 +  T cell exhaustion and immune resistance in GC.

CD8+ T cells are crucial cytotoxic components of the tumor immune system. In chronic inflammation, they become low-responsive, a state known as T cell exhaustion (TEX). The aim of immune checkpoint blockade is to counteract TEX, yet its dynamics in breast cancer remain poorly understood. This review defines CD8+ TEX and outlines its features and underlying mechanisms. It also discusses the primary mechanisms of CD8+ TEX in breast cancer, covering inhibitory receptors, immunosuppressive cells, cytokines, transcriptomic and epigenetic alterations, metabolic reprogramming, and exosome pathways, offering insights into potential immunotherapy strategies for breast cancer.

CD8 + T cells, a cytotoxic T lymphocyte, are a key component of the tumor immune system, but they enter a hyporeactive T cell state in long-term chronic inflammation, and how to rescue this depleted state is a key direction of research. Current studies on CD8 + T cell exhaustion have found that the mechanisms responsible for their heterogeneity and differential kinetics may be closely related to transcription factors and epigenetic regulation, which may serve as biomarkers and potential immunotherapeutic targets to guide treatment. Although the importance of T cell exhaustion in tumor immunotherapy cannot be overstated, studies have pointed out that gastric cancer tissues have a better anti-tumor T cell composition compared to other cancer tissues, which may indicate that gastrointestinal cancers have more promising prospects for the development of precision-targeted immunotherapy. Therefore, the present study will focus on the mechanisms involved in the development of CD8 + T cell exhaustion, and then review the landscapes and mechanisms of T cell exhaustion in gastrointestinal cancer as well as clinical applications, which will provide a clear vision for the development of future immunotherapies.

Background Dysfunction of CD8+ T cells in the tumor microenvironment (TME) contributes to tumor immune escape and immunotherapy tolerance. The effects of hormones such as leptin, steroid hormones, and glucocorticoids on T cell function have been reported previously. However, the mechanism underlying thyroid‐stimulating hormone (TSH)/thyroid‐stimulating hormone receptor (TSHR) signaling in CD8+ T cell exhaustion and tumor immune evasion remain poorly understood. This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8+ T cells and immune evasion in colorectal cancer (CRC). Methods TSHR expression levels in CD8+ T cells were assessed with immunofluorescence and flow cytometry. Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8+ T cells. Mechanistic insights were mainly gained through RNA‐sequencing, Western blotting, chromatin immunoprecipitation and luciferase activity assay. Immunofluorescence, flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues. Results TSHR was highly expressed in cancer cells and CD8+ T cells in CRC tissues. TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8+ T cell exhaustion. Conditional deletion of TSHR in CD8+ tumor‐infiltrating lymphocytes (TILs) improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1 (PD‐1) and hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3) through the protein kinase A (PKA)/cAMP‐response element binding protein (CREB) signaling pathway. CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8+ T cells, resulting in immunosuppression in the TME. Myeloid‐derived suppressor cells (MDSCs) was the main source of TSH within the TME. Low expression of TSHR in CRC was a predictor of immunotherapy response. Conclusions The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8+ T cell exhaustion and immune evasion in CRC. TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.

Cytotoxic T cells (CD8 + ) play a pivotal role in immunosurveillance by identifying and eliminating tumor cells. However, the onset of CD8 + T cell exhaustion, characterized by overexpression of immune checkpoint receptors, impairs their function, allowing tumor cells to evade immunosurveillance. Single-cell metabolic profiles hold the promise in characterizing intrinsic cellular metabolic heterogeneity of exhausted CD8 + T cells, even at ultra-early time points. Herein, we developed a multi-modal single-cell platform that integrates nanoparticles-enhanced laser desorption/ionization mass spectrometry and protein number counting platform to elucidate the temporal dynamics of CD8 + T cell exhaustion. A comprehensive time-series analysis was conducted, with nearly 3000 single cells performing metabolic profile extraction and checkpoint receptors quantification. Our results demonstrated that the onset of exhaustion was as early as 3 h post-stimulation and upon cessation of stimulation, a degree of reversibility was observed in these exhausted cells. Using deep learning algorithms, the discrimination of the different exhausted CD8 + T cell subpopulations from the control achieved an area under the curve value of more than 0.904, even to 1.000 with 100% sensitivity and specificity. Our work presents a robust, high-throughput, and scalable system for multi-modal single-cell analysis, offering valuable insights into the dynamics of CD8 + T cell exhaustion.

In the tumor microenvironment, T cells, B cells, and many other cells play important and distinct roles in anti‐tumor immunotherapy. Although the immune checkpoint blockade and adoptive cell transfer can elicit durable clinical responses, only a few patients benefit from these therapies. Increased understanding of tumor‐infiltrating immune cells can provide novel therapies and drugs that induce a highly specific anti‐tumor immune response to certain groups of patients. Herein, the recent research progress on tumor‐infiltrating B cells and T cells, including CD8+ T cells, CD4+ T cells, and exhausted T cells and their role in anti‐tumor immunity, is summarized. Moreover, several anti‐tumor therapy approaches are discussed based on different immune cells and their prospects for future applications in cancer treatment. The progress of anti‐tumor immunity is reviewed. Recent findings of CD4+ T cell, CD8+ T cell, T cell exhaustion and B cell are provided. Several anti‐tumor immunotherapies based on different immune cells in these years and prospects of anti‐tumor immunotherapies are also discussed. The clinical trials of some immunotherapies are also reviewed.