Summary: This study investigates the epigenetic landscape of exhausted CD8+ T cells in cancer and chronic viral infection models, revealing distinct accessible chromatin patterns compared to functional memory cells. The research identifies exhaustion-specific enhancer modules, including one that regulates PD-1 expression and contains motifs for RAR, T-bet, and Sox3. The findings suggest that these functional enhancer maps could serve as targets for genome editing to modify gene expression specifically in exhausted T cells.

Summary: This study defines PD-1+ TCF1+ CD8 T cells as 'resource cells' in chronic LCMV infection, which are crucial for the proliferative response following PD-1 blockade and are also found in cancer. These cells possess stem-like properties, self-renewing and differentiating into terminally exhausted CD8 T cells. Using ATAC-seq, the research compared the epigenetic signatures of stem-like versus exhausted CD8 T cells, revealing that stem-like cells exhibit unique accessibility patterns linked to HMG (TCF) and RHD (NF-κB) transcription factors, whereas exhausted cells show greater accessibility to ETS and RUNX motifs.

Summary: This study utilized single-cell transcriptome analysis of tumor-infiltrating CD8+ T cells from human melanoma and non-small cell lung cancer (NSCLC) to identify factors promoting T cell exhaustion. The researchers found that TOX, a transcription factor, was consistently upregulated as T cells became more exhausted and correlated with increased expression of inhibitory checkpoint molecules like PD-1, TIM-3, TIGIT, and CTLA-4. Knockdown of TOX led to downregulation of these inhibitory receptors, suggesting TOX promotes exhaustion by upregulating them. Furthermore, TOX levels in tumor-infiltrating T cells proved to be a strong predictor of patient survival and response to anti-PD-1 immunotherapy, indicating TOX as a potential therapeutic target and a biomarker for patient stratification.

Summary: This study investigates the role of histone lysine methyltransferase Suv39h1 in regulating CD8+ T cell responses to anti-PD-1 therapy in melanomas. The researchers found that inhibiting Suv39h1 delays tumor growth and enhances tumor rejection by anti-PD-1, leading to the survival and differentiation of effector cells that express IFNγ and Granzyme B, but do not reach terminal exhaustion. These cells exhibit alternative activation pathways and their transcriptional program correlates with clinical responders to immune-checkpoint blockade, identifying them as a potential biomarker. Mechanistically, anti-PD-1 treatment promotes chromatin opening in T-cell activation loci, and in the absence of Suv39h1, this opening shifts towards cytolytic effector loci, suggesting Suv39h1 acts as an epigenetic checkpoint that can be targeted to improve anti-tumor immunity.

Summary: This review discusses the differentiation of CD8+ T cells into terminally exhausted states within the tumor microenvironment (TME) and how immune checkpoint blockade (ICB) therapies targeting inhibitory receptors can reinvigorate these cells. It highlights the critical role of epigenetics, particularly through technologies like ATAC-seq, in enforcing T cell exhaustion phenotypes and identifies specific epigenetic alterations and transcription factors involved. The paper also explores epigenetic reprogramming as a promising strategy for developing novel immunotherapies against exhausted T cells.

Summary: This study investigated T cell dysfunction and recovery in individuals treated early for HIV infection (PHI) with antiretroviral therapy (ART). Researchers found that while ART led to partial normalization of immune checkpoint receptor (ICR) expression (PD1, Tim-3, TIGIT), epigenetic features associated with T-cell exhaustion, typically seen in chronic HIV, were already present early in PHI and only partially shifted towards a more favorable memory epigenome after three years of ART. These findings suggest that early ART can partially resolve HIV-related phenotypic and epigenetic changes, but complete resolution of exhaustion-associated epigenetic marks may not occur.

Summary: This review discusses how the lymphocytic choriomeningitis virus (LCMV) model system has been crucial in establishing fundamental concepts of T cell exhaustion, uncovering its complexity, regulators, and consequences. The findings from LCMV infections are directly applicable to understanding ineffective T cell responses in chronic infections like HIV and HCV, as well as in cancer. The paper highlights that exhausted T cells are characterized by a loss of effector functions and emphasizes how LCMV research has informed the development of checkpoint blockade therapies, particularly PD-1 inhibition, for reversing T cell exhaustion and improving cellular immunity in persistent antigen settings.

Summary: This review focuses on the critical role of exhausted CD8+ T cells as a major impediment to effective cancer immunotherapy. It highlights that while immunotherapy has shown significant promise, a substantial portion of patients do not respond or experience adverse effects, often due to T-cell exhaustion within the immunosuppressive tumor microenvironment. The paper discusses current research into the intrinsic and extrinsic mechanisms governing this exhaustion, including transcriptional and epigenetic alterations identified through techniques like single-cell RNA sequencing and mass cytometry, as well as metabolic changes. It also reviews ongoing clinical trials and hypothetical treatment strategies aimed at reinvigorating these exhausted T cells to improve therapeutic outcomes.

Summary: This review focuses on strategies to reinvigorate exhausted CD8+ T cells (CD8+ TEXs) within the tumor microenvironment (TME), a state characterized by impaired function and increased co-inhibitory receptor expression, which is linked to poor clinical outcomes in various cancers. The paper highlights that CD8+ TEXs are key responders to immune checkpoint blockade (ICB), but many patients do not achieve durable responses, necessitating improved strategies. It categorizes current approaches into ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy, and cytokine therapy, summarizing their efficacy, mechanisms, and potential for monotherapy or combination therapy to enhance anti-tumor immunity.

Summary: This review discusses how T cell exhaustion, a key limitation in cancer immunotherapy efficacy, is driven by the tumor microenvironment and the epigenetic landscape. It summarizes the epigenetic mechanisms that contribute to T cell exhaustion and explores the therapeutic potential of targeting epigenetic regulators to reinvigorate T cells, outlining future treatment paradigms that combine immunostimulatory agents with epigenetic therapies.

Summary: This study investigated the role of transcription factors (TFs) and epigenetic modulators in CD8 T cell fate decisions using in vivo CRISPR-Cas9 perturbation sequencing. The research found that knockout of the TF Klf2 led to aberrant differentiation into exhausted-like CD8 T cells during acute LCMV infection. Specifically, KLF2 was identified as crucial for suppressing the exhaustion-promoting TF TOX and enabling the TF TBET to drive effector differentiation, thereby maintaining effector CD8 T cell lineage fidelity and suppressing the exhaustion program.

Summary: This review summarizes the critical roles of epigenetic mechanisms in cancer initiation, progression, and immune cell function, highlighting how epigenomic dynamics influence cancer cell immunogenicity and immune cell fate. It details how epigenetic modifications regulate key immune-associated genes and immune checkpoint molecules like PD-1 and CTLA-4. The paper emphasizes that therapeutic strategies employing epigenetic modulating drugs can significantly alter the tumor microenvironment by reprogramming immune cells, inhibiting immunosuppressive populations, activating anti-tumor T cells and APCs, and enhancing tumor immunogenicity through mechanisms like de novo antigen expression and improved MHC presentation, ultimately aiming to improve cancer immunotherapy efficacy.

Summary: This mini-review explores the interplay between epigenetic regulation and CD8+ T-cell exhaustion in cancer immunotherapy. It highlights how DNA methylation, histone modification, and chromatin architecture provide insights into T-cell differentiation and exhaustion, emphasizing the critical need for strategies that dynamically govern epigenetic switches to maintain T-cell effector function. The paper discusses enzymatic factors and microRNAs that imprint T-cell epigenomes, driving exhaustion, and reviews recent advances in epigenetic interventions aimed at rescuing CD8+ T-cell functions, suggesting that modulating epigenetic changes and transcriptional programs has significant translational implications for cancer treatments.

Summary: This paper utilizes epigenetic profiling to suggest that exhausted T cells represent a distinct cell lineage, implying that their epigenetic state may influence the durability of therapeutic responses, such as those induced by PD-1 blockade.

Summary: This study investigated the early divergence of CD8+ T cell differentiation in acute versus chronic viral infections using single-cell RNA-sequencing and ATAC-sequencing on cells responding to LCMV-Armstrong (acute) and LCMV-Clone 13 (chronic). The findings indicate that CD8+ T cells in chronic infections exhibit earlier transcriptional and epigenetic changes, expressing higher levels of exhaustion-associated transcription factors and Ezh2, a key epigenetic regulator involved in silencing. Modulation of Ezh2 affected exhaustion-associated molecule expression, suggesting its role in shaping T cell fate during chronic infection, though context-dependency is noted.

Summary: This review examines CD8+ T cell exhaustion in anti-tumor immunity, a state characterized by reduced effector function, upregulation of inhibitory receptors, and altered transcriptional and epigenetic profiles, which impairs tumor control. It compiles current knowledge on the molecular mechanisms, including immune checkpoints, tumor microenvironment, metabolic reprogramming, transcription factors, and epigenetic modifications, and evaluates emerging therapeutic approaches such as immune checkpoint modulation, metabolic/transcriptional targeting, epigenetic editing, and CAR-T cells. The review also broadens the concept of exhaustion to other immune cells and proposes future research directions to improve cancer immunotherapy outcomes.

Summary: This study investigates the role of mSWI/SNF chromatin remodeling complexes in T cell activation and exhaustion, identifying that their stepwise localization to transcription factor binding sites dictates site-specific chromatin accessibility and gene activation. Perturbing these complexes, either genetically or pharmacologically, was shown to enhance T cell persistence, reduce exhaustion hallmarks, and improve memory features in vitro and in vivo. Furthermore, inhibiting mSWI/SNF complexes improved CAR-T cell expansion and anti-tumor efficacy, suggesting that targeting these complexes could be a viable strategy to enhance immunotherapy protocols.

Summary: This review examines the mechanisms of T-cell exhaustion in pancreatic cancer (PDAC), a state characterized by dysfunctional T cells and poor prognosis, often linked to an imbalance of inhibitory and stimulatory signals and high expression of receptors like PD-1, CTLA-4, TIM-3, and Lag-3. Despite efforts with immune checkpoint inhibitors, PDAC remains largely unresponsive, indicating complex underlying molecular drivers. Recent transcriptomic and epigenomic studies highlight the critical role of Thymocyte selection-associated high mobility group box protein (TOX) and its pathways in driving T-cell exhaustion in both chronic infection and cancer. The paper aims to review molecular, genetic, and cellular factors contributing to T-cell exhaustion in PDAC, alongside the effects of current immune checkpoint inhibitors and emerging therapies targeting these factors.

Summary: This review summarizes recent discoveries regarding the transcriptional regulatory network that governs the generation and propagation of exhausted CD8+ T cells, which arise from chronic infection and persistent antigenic stimulation. It highlights that these cells, previously considered defective, may be purposefully generated to provide milder, safer immune responses and can self-renew like stem cells. Key pathways identified involve T cell receptor (TCR) signaling leading to NFAT-TCF1 activity, followed by activation of the TOX/NR4A axis, aiming to advance strategies against cancer.

Summary: This review explores T cell differentiation and exhaustion, states of hypo-responsiveness that limit effector function in chronic infections and cancer. It highlights how recent advancements in CAR-T cell therapy for hematologic malignancies leverage T cell biology principles. The paper aims to summarize foundational concepts of T cell differentiation and exhaustion, and discuss how these can be targeted to enhance the design and efficacy of next-generation CAR-T cell therapies for improved cancer treatment.

Summary: This review elucidates the heterogeneity and hierarchical transcriptional regulation of T cell exhaustion, a state characterized by hypofunctionality and multiple inhibitory receptors that hinders immune checkpoint blockade (ICB) efficacy. It summarizes factors and signaling pathways that induce exhaustion, alongside epigenetic and metabolic alterations in exhausted T cells, and discusses how PD-1 signaling influences the balance between T cell activation and exhaustion, aiming to identify new therapeutic targets for combinational immunotherapies.

Summary: This study investigates CD8+ T-cell exhaustion in the tumor microenvironment, confirming that antigen recognition is required for this state. Using transcriptional and chromatin accessibility profiling, the research identifies the transcription factor NFAT as a promoter of T-cell exhaustion and highlights Nr4a transcription factors as potential new targets. While anti-PD-L1 therapy was examined for its effects on gene expression and chromatin accessibility in exhausted cells, the abstract notes only modest functional impacts without major chromatin changes.

Summary: This review discusses T cell hyporesponsiveness, specifically CD8+ T cell exhaustion observed during persistent antigen stimulation in chronic infections and cancer, and anergy induced by lack of costimulation. It highlights the role of inhibitory cell-surface receptors such as PD-1, LAG-3, CTLA-4, and TIM-3, and the clinical success of checkpoint blockade therapies that target these receptors to reverse hyporesponsiveness and promote tumor rejection. The paper reviews recent molecular insights into these states, covering transcription factors, metabolic programs, and changes in chromatin accessibility, and examines how checkpoint blockade therapies impact the molecular programs of CD8+ T cell exhaustion.

Summary: This review provides a comprehensive overview of how epigenetic modifications, including histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs, are dysregulated in human cancers and influence tumor immunogenicity and immune cell responses within the tumor microenvironment (TME). It highlights the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy, emphasizing the complex interplay between epigenetics and cancer immunology for developing combined therapeutic strategies.

Summary: This study investigates the role of epigenetic reprogramming, specifically DNA methylation of Runx3, in enhancing CD8+ T-cell function and response to PD-1 blockade immunotherapy in Hodgkin lymphoma patients. Combining decitabine (DAC) with anti-PD-1 therapy significantly improved complete response rates, suggesting a link between epigenetic regulation and immunotherapy efficacy. Multi-omics analysis revealed that reversing Runx3 promoter methylation promoted CD8+ T-cell infiltration and mitigated exhaustion. Experiments in Runx3-knockout mice confirmed Runx3's importance in CD8+ T-cell infiltration, differentiation, and response to DAC-primed immunotherapy, indicating Runx3's potential as a biomarker for predicting clinical response.

Summary: This paper investigates T cell exhaustion, a state characterized by impaired function and elevated inhibitory receptors, which compromises CAR-T cell therapy efficacy in cancer. It categorizes exhausted T cells into three subsets (progenitor, intermediate, terminal) regulated by transcriptional and epigenetic modulators. Key transcription factors such as TCF1, BACH2, and TOX, along with epigenetic regulators like TET2 and DNMT3A, are identified as crucial drivers of these exhaustion phenotypes. The study highlights the interplay of these molecular mechanisms within CAR-T research, suggesting potential for improved tumor treatment strategies.

Summary: This review discusses the critical role of epigenetic modifiers, such as SETDB1 and LSD1, at the intersection of cancer epigenetics and immune checkpoint inhibitor (ICI) therapy. It highlights how these epigenetic regulators can silence endogenous antigens, and their modulation can induce viral mimicry responses, thereby improving ICI efficacy in "cold" tumors. Furthermore, the paper points to the emerging role of epigenetic enzymes in establishing and maintaining stem-like T-cell populations, which are crucial for sustained responses to ICI, suggesting that targeting these epigenetic mechanisms holds significant potential for next-generation immuno-oncology treatments.

Summary: This review discusses the triphasic pathway of T-cell activation, proliferation, and differentiation leading to exhaustion in chronic infection, autoimmunity, and cancer. It highlights that exhausted T cells exhibit diminished effector functions, altered transcriptional networks, epigenetic signatures, and increased coinhibitory receptor expression. The review examines the establishment of exhaustion, the potential contribution of exhausted T cells to host control, their heterogeneity, and how checkpoint blockade therapies engage different exhausted T cell subsets to restore function.

Summary: This study establishes a novel in vitro system to rapidly induce CD8+ T cell exhaustion by repeated stimulation, mimicking the phenotype and transcriptomic profile of exhausted cells from chronic LCMV infections. The researchers found that Tcf7 promoter DNA methylation contributes to TCF1 downregulation in these in vitro exhausted T cells. This system is proposed as a valuable tool for identifying exhaustion-related genes and pathways, and for screening therapeutic agents aimed at reversing or preventing T-cell exhaustion.

Summary: This study investigates the role of BET inhibitors (BETi) in overcoming anti-PD1 resistance in CD8+ T cells from acute myeloid leukemia (AML) models and patients. The researchers found that BETi treatment reversed CD8+ T cell exhaustion, restoring proliferative capacity and enhancing the pool of precursor-exhausted T cells. Combined BETi and anti-PD1 therapy synergized in vivo, leading to reduced leukemia burden and improved T cell function, characterized by increased expression of Tcf7, Slamf6, and Cxcr5. Single-cell ATAC-seq revealed that BETi treatment specifically increases TCF7 accessibility in exhausted T cells, suggesting a mechanism where BETi relieves repression of progenitor programs in these cells, thereby maintaining a population responsive to anti-PD1 therapy.

Summary: This study investigated the epigenetic mechanisms underlying T-cell exhaustion in cancer by profiling histone modifications in tumor-infiltrating CD8 T cells. It found that terminally exhausted T cells exhibit chromatin features that restrict their transcriptional potential, with active enhancers lacking correlated gene expression, which could be restored by immunotherapeutic costimulatory signaling. The research also identified an increase in histone bivalency, linked to hypoxia exposure, as a driver of epigenetic repression. These findings suggest that both suboptimal costimulatory signals and environmental factors like hypoxia contribute to the functional impairment of exhausted T cells, and that these cells may retain latent transcriptional capacity if costimulatory signals are enhanced and hypoxia is reduced.

Summary: This literature review focuses on CD8+ T cell exhaustion, a state of dysfunction observed during chronic infections and tumor progression, characterized by reduced effector function, elevated inhibitory receptors, distinct metabolic profiles, and altered transcriptional signatures. The paper highlights recent advancements in understanding and targeting the regulatory mechanisms of T cell exhaustion, particularly in the context of tumor immunotherapy, and discusses the potential for reversing this state with clinical implications.

Summary: This study investigates the role of Nr4a transcription factors (Nr4a1, Nr4a2, Nr4a3) in CD8+ T cell exhaustion within a murine CAR T cell melanoma model. Researchers observed that exhausted CAR T cells and endogenous tumor-infiltrating lymphocytes (TILs) with low effector function and high inhibitory receptor expression exhibited similar gene expression and chromatin accessibility profiles, linked to Nr4a activation. A comparison with human CD8+ TILs and HIV-infected T cells also revealed high Nr4a expression and Nr4a binding motifs in accessible chromatin. Importantly, CAR T cells engineered to lack Nr4a transcription factors (Nr4a TKO) demonstrated improved anti-tumor efficacy, with tumor regression and prolonged survival in mice, suggesting Nr4a inhibition as a potential therapeutic strategy for enhancing cancer immunotherapy.

Summary: This review discusses melanoma, a malignant skin cancer characterized by immune escape, and highlights the efficacy of immune checkpoint blockades in reinvigorating exhausted immune cells. It explores the pivotal role of epigenetics, including DNA methylation and histone modifications, in regulating tumor cell behaviors and contributing to melanoma progression. The paper aims to systematically summarize the intricate linkage between epigenetics and antitumor immunity in melanoma, examining its implications for immunotherapy and reviewing clinical trials of epigenetics-based melanoma treatments.

Summary: This study investigated the epigenetic basis for differential responses to anti-PD-1 therapy in gastric cancer (GC) patients by analyzing the genome-wide chromatin accessibility of circulating CD8+ T cells using ATAC-seq. The researchers identified distinct open chromatin regions that differentiate responders from non-responders, finding that higher overall chromatin openness in CD8+ T cells correlated with a better response and improved survival. The findings suggest that baseline epigenetic characteristics of CD8+ T cells can predict which metastatic GC patients are likely to benefit from anti-PD-1 therapy.

Summary: This study investigates the role of the immunometabolite L-2-hydroxyglutarate (L-2-HG) in T cell exhaustion, examining its presence in patients with HIV infection, chronic leukemia, and hepatocellular carcinoma. Using RNA-seq and ATAC-seq, the researchers identified epigenetic signatures and transcriptome alterations in exhausted T cells (Tex), noting mitochondrial dysfunction and reduced L-2-HG levels, along with increased H3K27me3. In vitro experiments showed that L-2-HG treatment improved mitochondrial metabolism, decreased H3K27me3, and promoted memory T cell differentiation in Tex. Furthermore, in a mouse melanoma model, L-2-HG-treated CD8+ T cells enhanced effector function and reduced tumor volume, demonstrating L-2-HG's potential to reverse T cell exhaustion via epigenetic modifications and improve anti-tumor immunity.

Summary: This review explores how epigenetic programs, regulated by chromatin-modifying enzymes like histone acetyltransferases and deacetylases, control CD8+ T cell identity and function. It highlights the critical dependence of these enzymes on metabolic products such as acetyl-CoA, NAD, and S-adenosylmethionine, indicating a significant crosstalk between cellular metabolism and epigenetic regulation. The paper further examines how metabolic signals, especially those from the tumor microenvironment, shape the epigenetic landscape of CD8+ T cells, offering insights into the mechanisms underlying T-cell exhaustion in anti-tumor and anti-viral immunity and potential strategies to improve T-cell-based therapies.

Summary: This study identifies genes associated with T-cell exhaustion (Tex) in lung adenocarcinoma using weighted correlation network analysis. A prognostic signature comprising nine key genes was developed via random forest and LASSO regression, classifying patients into low- and high-risk groups. The risk score was validated as an independent prognostic factor across multiple cohorts and correlated with immune response metrics, predicting better outcomes for the low-risk group in response to immune checkpoint inhibitors (ICIs). The research also explored differential drug sensitivities and constructed a nomogram for clinical application.

Summary: This study analyzed single-cell RNA sequencing data from hepatocellular carcinoma (HCC) patients to understand T cell subsets within the tumor microenvironment. Researchers examined CD3+ cells from tumor tissues, adjacent normal tissues, and peripheral blood, identifying 10 distinct cell clusters. Key findings indicate transitional states of exhausted CD8+ T cells (Tex) and regulatory T cells (Tregs) are enriched in tumor tissue, with Tex accumulation and location correlating with clinical outcomes. The data revealed that transitioning Tex cells co-express effector molecules and inhibitory receptors, and early exhaustion stages involve changes in stress response and cell cycle genes, while Tregs show profound activation. The study concludes that T cell exhaustion is a progressive process, distinct from anergy, potentially driven by a combination of passive defects and overactivation, offering insights for cancer immunotherapy development.

Summary: This study investigated the expression of transposable elements (TEs) in CD8+ T cells undergoing exhaustion in chronic viral infections and cancer models, using bulk and single-cell transcriptomics. It found that specific TEs, like murine VL30, are repressed in terminally exhausted T cells but their expression is driven by the transcription factor Fli1 in early exhausted T cells. Importantly, immune checkpoint blockade (ICB) therapy, such as anti-PD-1, increased TE expression in both mouse and human tumor-infiltrating lymphocytes, suggesting TEs could serve as biomarkers for ICB response and offering insights into immune cell identity and heterogeneity during exhaustion and therapeutic reprogramming.

Summary: This study explores an epigenetic mechanism underlying T-cell exhaustion in cancer, specifically focusing on tumor-infiltrating lymphocytes (TILs). It identifies that environmental stress can lead to epigenome remodeling in TILs, partly due to the loss of the histone methyltransferase EZH2. The research reveals a Cdkn2a.Arf-mediated pathway, independent of p53, where EZH2 inhibition results in mitochondrial dysfunction and subsequent T-cell exhaustion. Furthermore, the study demonstrates that reprogramming T cells to express a gain-of-function EZH2 mutant enhances their anti-tumor activity.

Summary: This review discusses how chronic exposure to antigens or inflammatory signals in cancer and viral infections leads to T-cell exhaustion, characterized by epigenetic and metabolic alterations. It highlights the discovery of immune checkpoint pathways and therapies targeting them, noting limitations such as transient effects and heterogeneity, which may stem from irreversible epigenetic changes. The paper emphasizes the utility of ATAC-seq in analyzing chromatin accessibility to understand these dynamic epigenetic modifications during T-cell exhaustion, aiming to provide molecular insights, identify new therapeutic targets for chronic infections and cancer, and inform the design of more effective immunotherapies.

Summary: This study investigates T-cell exhaustion in regulatory T cells (Tregs) by expressing a tonic-signaling chimeric antigen receptor (TS-CAR), a method known to induce exhaustion in conventional T cells. The TS-CAR-expressing Tregs exhibited an exhaustion phenotype with significant changes in their transcriptome, metabolism, and epigenome, including upregulation of inhibitory receptors like PD-1 and transcription factors such as TOX and BLIMP1, alongside increased chromatin accessibility at AP-1 binding sites. While these Tregs maintained suppressive function in vitro, they were nonfunctional in vivo in a xenogeneic graft-versus-host disease model, highlighting Treg susceptibility to chronic stimulation-driven dysfunction and its implications for CAR Treg immunotherapy design.

Summary: This study investigated the epigenetic mechanisms driving the upregulation of immune checkpoints (PD-1, CTLA-4, PD-L1) and T cell exhaustion markers (TIM-3, TOX2) in colorectal cancer (CRC) patients. Using quantitative real-time reverse transcriptase PCR, researchers found significantly elevated mRNA levels of these markers in CD4+ and CD8+ tumor-infiltrating lymphocytes and bulk CRC tumor tissues. Epigenetic analysis via bisulfite sequencing and ChIP-qPCR revealed downregulated histone 3 lysine 9 trimethylation and upregulated histone 3 lysine 4 trimethylation at the promoters of PD-L1 and TOX2, suggesting that activating epigenetic modifications contribute to their increased expression. The findings imply that epigenetic modifiers could be a therapeutic strategy to enhance anti-tumor immunity in CRC.

Summary: This review examines the molecular mechanisms of T-cell exhaustion within the tumor microenvironment (TME), a key factor limiting cancer immunotherapy efficacy. It details how TME components interact with inhibitory receptors on T cells, leading to altered transcriptomes, epigenomes, and metabolism, ultimately causing T-cell exhaustion, which is characterized by distinct pre-exhausted and terminally exhausted states. The paper also discusses potential intervention strategies aimed at reversing T-cell exhaustion to enhance immunotherapy outcomes in cancer treatment.

Summary: This review summarizes the epigenetic changes associated with CD8 T cell exhaustion, a state induced by chronic antigen exposure in settings like tumors and viral infections. It highlights how environmental signals drive distinct epigenetic landscapes that promote a trajectory toward dysfunction, differing from effector and memory cell differentiation. The paper also discusses immunotherapeutic strategies targeting these epigenetic modifications and inhibitory receptors as potential avenues for reversing T-cell exhaustion.

Summary: This review examines how metabolic reprogramming influences T cell activation, differentiation, and immune responses, particularly focusing on T cell exhaustion during chronic infections. It highlights the distinct metabolic profiles of progenitor exhausted T cells (utilizing FAO and OXPHOS) and terminally exhausted T cells (relying on impaired glycolysis and OXPHOS). The paper also reviews how metabolic-related factors, including antigen stimulation, cytokines, and epigenetics, affect T cell exhaustion, and discusses intervention strategies targeting metabolism and epigenetics to reverse this state.

Summary: This review explores the role of epigenetic mechanisms in shaping the tumor microenvironment and antitumor immunity, with a particular focus on how DNA modifications, histone modifications, and epitranscriptome regulations influence various immune cells, including T cells, within the context of cancer. It highlights the potential of epigenetic therapies to enhance cancer immunotherapies by targeting these immune cell dysregulations and suggests future directions for combination therapies.

Summary: This paper highlights T cell exhaustion as a key feature of cancer and chronic viral infections, emphasizing that revitalizing exhausted T cells is crucial for immune restoration and disease cure. It posits that epigenetic mechanisms play a direct role in the transcriptional control of T cell exhaustion, and understanding the exhausted T cell epigenome is a critical step for developing therapeutic strategies to overcome this state in both infections and cancer.

Summary: This review examines the control of transcriptional networks, including the induction of inhibitory receptors, by T cell-specific transcription factors in exhausted T cells found in chronic viral infections like HIV. It notes that transcriptional profiling reveals distinct molecular phenotypes for exhausted CD4 and CD8 T cells in these models, with several transcription factors like Blimp-1, BATF, and Helios implicated in promoting exhaustion. While no single factor is solely responsible, exhaustion appears to be a combinatorial mechanism involving multiple interacting transcription factors that influence the development of functionally exhausted T cells.

Summary: This review focuses on the transcription factor regulation of CD8+ T cell memory and exhaustion during infections. It highlights that chronic stimulation in persistent infections leads to the generation of exhausted CD8+ T cells, which exhibit distinct transcriptional profiles compared to naive and memory cells. The paper notes that while T-cell memory development has been extensively studied transcriptionally, T-cell exhaustion has received less attention. It emphasizes the role of transcription factors, identified through new computational methods, in controlling T-cell fate and state, suggesting that understanding these molecular processes could reveal therapeutic targets for infectious and immunological diseases.

Summary: This study investigated T cell dysregulation in Myalgic encephalomyelitis/chronic fatigue syndrome (ME) using multiomic analysis, including single-cell RNA-seq, RNA-seq, and ATAC-seq, with a focus on CD8+ T cells. The researchers found that specific CD8+ T cell subsets exhibited upregulation of transcription factors associated with T cell exhaustion, an altered chromatin landscape, and metabolic reprogramming indicative of an exhausted state. These findings were validated by flow cytometry, identifying T cell exhaustion as a component of ME and suggesting potential therapeutic avenues like checkpoint blockade.

Summary: This study investigated the chromatin accessibility of regulatory T cells (Tregs) within the murine tumor microenvironment (TME), comparing them to peripheral Tregs and assessing changes with anti-PD-1 immunotherapy. The findings revealed that Tregs in the TME possess a distinct chromatin accessibility signature compared to peripheral Tregs, characterized by reduced accessibility at loci associated with conventional CD4+ T cell effector function. While Tregs from skin-resident tumors showed similarities to naïve skin-resident Tregs, they still exhibited TME-attributable differences. Notably, the study concluded that Treg chromatin accessibility and transcriptome remained stable and unaltered by tumor type, time, or immunotherapy.