Intervertebral disc degeneration is characterized by the metabolic dysregulation of nucleus pulposus cells, which is regulated by complex post-translational modifications, manifesting as extracellular matrix remodeling and inflammatory microenvironment formation. We demonstrated the progressive downregulation of HDAC1 during disc degeneration. HDAC1 mediates the deacetylation and ubiquitination-dependent degradation of YBX1. The downregulation of HDAC1 results in YBX1 accumulation, compromising extracellular matrix synthesis in nucleus pulposus cells while enhancing the degradation processes. Furthermore, the accumulated YBX1 stimulates chemokine expression, facilitating the development of an inflammatory microenvironment. Targeting this critical axis, we developed SU056@GelMA to deliver the YBX1 inhibitor SU056, mitigating the metabolic disruption induced by YBX1 accumulation. Intervertebral disc degeneration (IVDD) is a leading cause of disability, with nucleus pulposus cells (NPCs) undergoing metabolic changes that lead to extracellular matrix (ECM) degradation and inflammation. This study explores the role of histone deacetylase 1 (HDAC1) in IVDD, revealing its downregulation in degenerative discs and its critical role in maintaining NPC metabolic homeostasis. Researchers used RNA sequencing and protein analysis to demonstrate that HDAC1 regulates ECM synthesis and degradation by deacetylating Y-box-binding protein 1 (YBX1), promoting its ubiquitination and degradation. HDAC1 deficiency led to YBX1 accumulation, promoting ECM degradation and inflammation. The study introduced SU056@GelMA, a hydrogel delivering the YBX1 inhibitor SU056, which improved ECM synthesis and reduced inflammation in rat and rabbit IVDD models. These findings highlight the potential of HDAC1 as a therapeutic target, suggesting future research on post-translational modifications in IVDD treatment. "This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author. "
Nuclear receptors are key effectors of metabolic programs; however, the contribution of co-regulatory complexes in maintaining metabolic homeostasis is not fully understood. Here, we show that modulation of the constitutive androstane receptor (CAR) by the co-repressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is required for bile acid (BA) homeostasis. Transcriptional changes in the livers of mice harboring a targeted disruption in one of the nuclear receptor-interacting domains (RIDs), SMRTmRID1 mice, revealed increased expression of CAR target genes involved in BA export. Consistent with this, SMRTmRID1 mice challenged with a high-fat diet showed increased BAs in serum and urine with commensurate decreases in the liver and intestines. Notably, the reduction in intestinal BAs led to decreased activity of the BA receptor farnesoid X receptor (FXR). This reduction in FXR activity compromised the integrity of the intestinal barrier, increased bacterial burden, and augmented intestinal inflammation. Moreover, SMRTmRID1 mice were susceptible to intestinal damage, with higher mortality rates in acute colitis and colitis-associated cancer models. Treatment with a synthetic FXR agonist (XL335) rescued SMRTmRID1 mice during acute colitis. Collectively, these studies highlight the importance of SMRT in maintaining BA homeostasis through direct and indirect regulation of hepatic CAR and intestinal FXR activity, respectively, and point to potential therapeutic routes for combating intestinal pathologies associated with a high-fat diet. Nuclear receptors (NRs) have a crucial role in gene transcription regulation, impacting metabolic homeostasis. This study explores the disruption of the silencing mediator for retinoid and thyroid hormone receptors (SMRT) network in high-fat diet (HFD)-fed SMRTmRID1 mice, revealing its impact on bile acid (BA) homeostasis and intestinal health. Researchers used SMRTmRID1 knock-in mice, which have mutations in the RID1 domain, to study the effects of impaired SMRT–NR interactions. They found that disrupted SMRT function derepresses hepatic constitutive androstane receptor activity, leading to altered BA metabolism and reduced intestinal BA levels. This reduction impairs farnesoid X receptor-mediated mucosal defense, increasing intestinal permeability and inflammation. The study highlights the importance of the SMRT–NR network in maintaining BA homeostasis and suggests that farnesoid X receptor activation could mitigate intestinal dysfunction. Future research could explore tissue-specific SMRT models to further understand these interactions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Despite significant biomedical advances, cardiovascular disease remains a leading cause of global mortality. The traditional 'bench-to-bedside' research pipeline, which heavily relies on animal models to guide clinical translation, is often hampered by species-specific physiological differences, leading to high rates of clinical trial failures. In this Review, we advocate for a paradigm shift toward a 'human-first' discovery approach. We explore how integrating human cardiac tissue resources obtained from biopsies, surgical explants and autopsies with high-resolution multi-omics technologies (including transcriptomics, proteomics and metabolomics) is transforming our understanding of complex heart diseases. We highlight recent breakthroughs in heart failure, ischemic heart disease, arrhythmias, myocarditis and valvular stenosis achieved through direct profiling of human samples. Finally, we propose a 'bedside-to-bench-and-back' strategy, in which therapeutic targets are identified in human tissues and then validated in animal models to accelerate the development of precise, clinically relevant cardiovascular treatments.
Exercise and cold exposure elicit partly overlapping metabolic adaptations through distinct mechanisms. Here, we sought to identify circulating factors shared by these stimuli. We found that exercise and cold exposure upregulated thrombospondin-1 (TSP1) expression in skeletal muscle and brown adipose tissue (BAT) and induced the release of its N-terminal fragment (N-TSP1). In high-fat-diet-induced obese mice, N-TSP1 administration enhanced muscle strength, increased energy expenditure and attenuated insulin resistance and hepatic steatosis. N-TSP1 also increased mitochondrial respiration and oxidative metabolism in skeletal muscle and stimulated thermogenic marker gene expression in brown adipocytes. In aged mice, N-TSP1 administration significantly improved physical performance and was associated with tissue-specific metabolic remodelling. In humans, plasma N-TSP1 levels correlated positively with muscle mass and physical performance. Together, these findings support a role for N-TSP1 as an exercise- and cold-responsive circulating factor that modulates skeletal muscle function and tissue-specific metabolic adaptation, with potential relevance to obesity- and age-related functional decline.
Neurological heterotopic ossification can rapidly arise in the periarticular muscles following spinal cord injury. However, the specific mechanism of how the injured central nervous system regulates heterotopic bone formation in peripheral tissues remains largely unexplored. Here we first demonstrate through single-cell RNA sequencing and spatial transcriptomic analysis that fibroadipogenic progenitor cells (FAPs) contribute to heterotopic ossification in injured muscle tissues following spinal cord injury. Mechanistically, we define a neuro-immune-bone axis in which endothelial tip cells within the injured spinal cord serve as a major source of adrenomedullin (ADM), which acts on muscle-resident regulatory T cells (Treg) through RAMP2, promoting their expansion and enhancing their pro-osteogenic phenotype characterized by increased BMP-2 and TGF-β production. These ADM-activated muscle-resident Treg subsequently promote the osteogenic differentiation of FAPs. Conditional knockout of Ramp2 on Treg or inhibition of spinal cord-derived ADM suppresses osteogenic differentiation of FAPs and subsequent neurological heterotopic ossification. Collectively, this work elucidates a mechanistic paradigm in which the injured central nervous system remotely orchestrates peripheral pathology through long-range cellular mediators, redefining our understanding of cross-system communication after neurologic damage.
KRAS is one of the most frequently mutated oncogenes in human cancers and plays a central role in regulating signaling pathways that control cell proliferation, survival and metabolism. Recent advances in allele-specific inhibitors, particularly those targeting KRASG12C, have demonstrated that direct pharmacological inhibition of KRAS is clinically feasible. However, the durability of therapeutic responses remains limited due to intrinsic and acquired resistance mechanisms, including secondary KRAS mutations, pathway reactivation and adaptive signaling rewiring. These challenges highlight the need for complementary strategies that extend beyond direct catalytic inhibition. The ubiquitin-proteasome system has emerged as a critical regulator of KRAS stability and signaling networks. Deubiquitinases (DUBs), which reverse ubiquitination and modulate protein turnover, have been increasingly recognized as key regulators of oncogenic signaling pathways upstream and downstream of KRAS. By influencing protein abundance, localization and signaling competence, DUBs can modulate pathway robustness and adaptive responses that contribute to therapeutic resistance. In this Review, we summarize current understanding of ubiquitin-dependent regulation in KRAS-driven cancers, focusing on DUBs and E3 ligases that directly control KRAS stability as well as those that regulate major KRAS effector pathways, including RTK-RAS, RAF-MEK-ERK and PI3K-AKT-mTOR signaling. We further discuss the therapeutic implications of DUB inhibition, its potential to overcome resistance and its relationship to emerging targeted protein degradation strategies.
There are only a few whole genome sequencing studies of human gastric cancer (GC) conducted so far. We performed comprehensive whole genome, bulk RNA, and methylation sequencing analyses of 100 samples of GC and adjacent normal tissue. In a smaller non-EBV/non-MSI subset (n = 23), we also performed proteomic profiling by mass spectrometry. We validated the proteomic findings in an independent dataset. Using this unprecedented dataset of human GC samples, we examined the extent of chromothripsis, homologous recombination deficiency, and retrotransposition, and correlated these events with patient outcomes. We found that chromothripsis occurred in 22% of GCs and correlated with poor prognosis. Multichromosomal chromothripsis was associated with a particularly high risk of death. Based on copy number (CN) signature analysis, we identified a distinct non-CN9 subgroup with significantly worse outcomes. Homologous recombination deficiency was present in 4% of GCs and was associated with overexpression of immune signaling pathways. Somatic retrotransposition events were most strongly associated with global hypomethylation. We also identified BYSL as a putative oncogenic driver within the 6p21 locus whose amplification is associated with poor prognosis. Collectively, our findings provide novel insights into the dysregulation of DNA stability and repair and their clinical relevance in human GCs.
Acute myeloid leukaemia (AML) remains a therapeutically challenging malignancy owing to its high relapse rates and chemoresistance, often linked to elevated antioxidant defences. Here, we demonstrate that bone marrow stromal cells (BMSCs) confer chemoresistance in AML by upregulating the purinergic receptor P2RX7. Blocking P2RX7 restored chemosensitivity of AML cells. Mechanistically, BMSC-mediated P2RX7 overexpression induces calcium influx and mitochondrial calcium overload, triggering mitochondrial stress and a compensatory antioxidant response. This process involves mitochondrial phosphoglycerate mutase 5 (PGAM5) transducing reactive oxygen species signals, interfering with Keap1-Nrf2 complex formation and leading to Nrf2 stabilization, thereby enhancing cellular antioxidant defences. These findings identify a vital role of P2RX7 in the BMSC-driven redox adaptation programme that underlies AML chemoresistance and highlight P2RX7 signalling as a potential therapeutic target.
Osteoarthritis (OA) is among the most prevalent chronic diseases worldwide. However, currently employed pharmacological therapies for OA are associated with various reported side effects. Exercise therapy represents a potentially safer and more effective strategy for OA treatment, although its underlying mechanism remains unclear. Here, we demonstrate that compared with high-intensity continuous training, moderate-intensity continuous training (MICT) has greater therapeutic potential for OA. Notably, these beneficial effects of MICT were abrogated following gut microbiota depletion. Moreover, transplantation of the gut microbiota from MICT-treated mice inhibited OA progression. Akkermansia was identified as the most significantly altered microbiota in response to MICT, and supplementation with Akkermansia in destabilization of the medial meniscus mice also alleviated OA. Mechanistically, MICT protects against OA by reducing plasma lactate levels. Production of high levels of lactate by numerous microbiotas was identified as a risk factor induced by destabilization of the medial meniscus. Consistent with these findings, our genetic data revealed that both the knockout of the lactate receptor Gpr81 and the knockdown of Gpr81 in articular cartilage with adeno-associated virus 2 mitigated OA progression by increasing anabolic metabolism and suppressing catabolic metabolism. The Gαi-CREB/NF-κB axis was further identified as the primary downstream pathway mediating the biological effects of Gpr81 in chondrocytes. Clinically, we validated a negative correlation between Akkermansia abundance and both synovial fluid lactate levels and GPR81 expression in the articular cartilage of OA patients. Collectively, the results of this study not only reveal the mechanism underlying the protective effects of exercise against OA but also identify a novel therapeutic target for OA treatment. Moderate-intensity continuous training remodelled the gut microbial composition in destabilization of the medial meniscus mice, which in turn decreased blood lactate levels, further alleviated destabilization of the medial meniscus-induced hyper-lactate and Gpr81 overactivation, ultimately ameliorating osteoarthritis by coordinating the Gαi-CREB/NF-κB signalling pathway.
Human renal proximal tubular epithelial cells (RPPTCs) are crucial for exploring the molecular and cellular mechanisms underlying the pathophysiology of kidney injuries. In this study, we generated the functionally enhanced kidney organoid-derived proximal tubule cells (FEKOPTCs) from human induced pluripotent stem cells. Heparan sulfate proteoglycans and transforming growth factor-β receptor inhibitor enhanced the functionality of PTCs isolated from the kidney organoids of which the vascularization and maturation were improved by heparan sulfate proteoglycans and vascular endothelial growth factor. FEKOPTCs showed significantly enhanced epithelial barrier function, polarization state, and transporter function, compared with primary human RPTECs, which led to improve the function of drug uptake. Transcriptomic characterization of FEKOPTCs revealed high similarity to PTCs of native human adult kidney. FEKOPTCs-on-chip are more sensitive predictors than RPTECs-on-chip for nephrotoxicity testing. By using CRISPR-Cas9 genetic mutation of alpha-galactosidase A, the causative gene of Fabry disease, alpha-galactosidase A-mutant FEKOPTCs, recapitulated the functional phenotype of Fabry disease. When FEKOPTCs were transplanted into the kidney parenchyma of NOD-SCID mice, they reassembled and regenerated proximal tubular structures with intact lumens and functional transporters. Taken together, our results suggest that FEKOPTCs are functionally enhanced PTCs and can be applied for nephrotoxicity testing, disease modeling, and regenerative medicine.
Antiviral innate immunity is a decisive determinant of whether cardiotropic viral infection resolves or progresses to myocarditis and deadly heart failure. Viral myocarditis (VM) remains a leading cause of sudden death in children and young adults, yet its human pathophysiological mechanisms remain incompletely understood and effective therapies are limited. In this Review, we map the cellular and molecular logic of cardiac antiviral innate immunity from first sensing to therapeutic opportunity and synthesize how these responses set the myocardial 'inflammatory set point' across cardiac-resident cells and recruited innate immune cells. We highlight RNA- and DNA-sensing immune signaling pathways that detect cardiotropic RNA and DNA viruses to collectively shape viral control and heart injury during VM. Finally, we connect mechanisms to translation by summarizing emerging biomarkers and clinical trials and by proposing a phase- and etiology-guided therapeutic framework that pairs antiviral immunomodulation with timely restraint of innate proinflammatory amplifiers to limit heart damage and prevent progression from VM to heart failure. This review will provide a roadmap of antiviral innate immunity to accelerate mechanistic discovery and targeted therapy for VM and virus-associated cardiovascular diseases.
To better understand diabetes and normoglycemia, pancreatic islet biology requires a precise molecular understanding of islet cell types at both the transcriptomic and proteomic levels. While transcriptomic analyses are well established, comprehensive proteomic characterization has been lacking, limiting our knowledge of islet molecular complexity. Here we introduce a nonenzymatic, mechanistic single-cell isolation technology using laser microdissection (LMD7), facilitating proteomic and transcriptomic analysis of physically isolated α-, β- and δ-cells from fresh-frozen, unfixed pancreatic tissue. This mechanistic approach avoids enzymatic digestion and chemical fixation, preserving the cells' native molecular state before processing. Given the limited existing proteomic data, we supplemented our findings with transcriptomic analysis generated using the same method and compared our results with data from enzymatically isolated cells, obtained by fluorescence-activated cell sorting and compiled by others. Our analysis revealed that enzymatic digestion alters gene expression patterns, particularly those of membrane-associated proteins, underscoring the impact of isolation techniques on biological outcomes. We identified cell-type-specific proteins typically underrepresented in pancreatic single-cell transcriptomic datasets. β-cells exhibited enrichment in vesicle trafficking proteins, α-cells displayed distinct calcium-dependent action potential machinery and δ-cells showed elevated expression of focal adhesion-related proteins. In addition, we report an inverse molecular relationship between β- and δ-cells, potentially driven by transcriptional regulators such as Mlxipl. By establishing robust molecular profiles directly from intact pancreatic tissue, this work provides a reference point for future pathological comparisons, offering a framework to investigate how diabetes and other endocrine disorders reshape islet cell biology.
Cancer cells undergo extensive metabolic reprogramming to sustain rapid proliferation and adapt to heterogeneous tumour microenvironments. These metabolic alterations are tightly linked to epigenetic regulation, which reshapes gene expression and cellular signalling mechanisms. Among epigenetic regulators, histone deacetylases (HDACs) have emerged as key modulators of cancer metabolic reprogramming. Along with their canonical roles in histone deacetylation, HDACs regulate non-histone substrates, including metabolic enzymes and transcription factors, thereby coordinating transcriptional and metabolic programmes. In this review, we summarize current insights into HDAC-mediated regulation of glucose, lipid and amino acid metabolism in cancer and discuss the metabolic mechanisms underlying the anticancer effects of HDAC inhibitors. Collectively, we propose an integrated framework in which HDACs function as central regulators of cancer metabolic reprogramming. We highlight the limitations of HDAC inhibitor studies and discuss the emerging importance of isoform-specific HDAC functions in reprogramming cancer-specific metabolic dependencies and therapeutic strategies.
Although oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed owing to oxaliplatin resistance. The roles of long non-coding RNAs-encoded microproteins in oxaliplatin chemoresistance remain inadequately explored. In this study, a CRISPR/Cas9 library was developed to target previously identified 314 microproteins translated from long non-coding RNAs, followed by functional screening. This strategy identified MKKS3, encoded by NR_072977, as a key regulator of chemoresistance in CRC. A pan-cancer analysis integrating translatomics and proteomics revealed widespread MKKS3 expression across various human cancers. Our experiments demonstrated that MKKS3 promotes chemoresistance in CRC and drives iCAF-to-myCAF conversion. Mechanistically, MKKS3 interacts with TRIM29 to facilitate DNA repair complex assembly and induce STING ubiquitination, thus suppressing IFNβ secretion and further activating fibroblasts. These activated fibroblasts secrete increased amounts of TGFβ, which in turn downregulates STING expression. Additionally, DENR functions as a suppressor of MKKS3 expression and regulates its translation. The natural compound 1-Hydroxybaccatin I inhibits the MKKS3-TRIM29 interaction, and its combination treatment with oxaliplatin enhances therapeutic outcomes of CRC by promoting CD8+ T cell activation and tumour infiltration. Moreover, intratumoural injection of AAV8-shMKKS3 with oxaliplatin produces a synergistic anti-tumour effect. Collectively, MKKS3 drives CRC chemoresistance through the TRIM29-STING-IFNβ-TGFβ axis. This study provides novel insights into the mechanism of MKKS3 in regulating chemoresistance and providing a potential therapeutic target for reversing the chemoresistance of CRC.
N-terminal acetyltransferase D (NatD) acetylates histones H4 and H2A at serine 1 and has been implicated in oncogenesis, yet its role in glioblastoma (GBM) remains unexplored. Here, we show that NatD expression is significantly elevated in GBM at both transcript and protein levels. NatD knockdown markedly suppressed proliferation, colony formation, migration, invasion and tumoursphere formation in GBM cell lines and patient-derived models, indicating a critical role in maintaining cancer stem-like properties. These inhibitory effects were rescued by reintroduction of wild-type NatD but not by a catalytically inactive mutant, confirming dependence on its enzymatic activity. Transcriptomic profiling identified fibroblast growth factor receptor (FGFR) 4 as a key downstream effector. Mechanistically, NatD maintained N-terminal acetylation of histones H4 and H2A at the FGFR4 promoter, thereby antagonizing casein kinase 2α-mediated phosphorylation and sustaining an open chromatin state permissive for transcription. NatD depletion reduced FGFR4 expression and downstream ERK1/2 and AKT phosphorylation, whereas FGFR4 overexpression restored malignant phenotypes suppressed by NatD knockdown both in vitro and in xenograft models. Orthotopic xenograft models further demonstrated that NatD depletion suppresses intracranial tumour growth and prolongs survival, whereas FGFR4 re-expression partially restores tumour progression. Analysis of TCGA GBM datasets revealed that the positive correlation between NatD and FGFR4 expression is maintained across multiple molecular subtypes. Collectively, these findings identify NatD as an oncogenic regulator of GBM and underscore NatD-FGFR4 signalling as a promising therapeutic target.
Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic dysregulation, with both prolyl hydroxylase domain protein 3 (PHD3) and pyruvate carboxylase (PC) independently implicated in disease progression. Although each influences patient outcomes, a direct mechanistic interplay between these two regulators has remained elusive. Here, we uncover a novel regulatory axis involving PHD3 and PC by identifying an unexpected subcellular behavior of PHD3, namely, its dual localization to the cytosol and the mitochondrial matrix. We show that mitochondrial import of PHD3 is associated with its intracellular clustering, a process modulated by PHD3 hydroxylase activity and oxygen levels. Once in the matrix, PHD3 directly hydroxylates PC, suppressing its enzymatic activity. In ccRCC with elevated PHD3 expression, this modification restricts anaplerotic flux into the tricarboxylic acid cycle, leading to impaired proliferation, reduced metastasis, and enhanced apoptosis. Together, our findings provide a new framework for targeting cancer metabolism by establishing a previously unrecognized mechanistic link between PHD3-mediated oxygen sensing within the tumor microenvironment and the regulation of ccRCC mitochondrial metabolism through the subcellular re-localization of PHD3.
Functionally mature hepatocyte generation requires coordinated genetic, metabolic, and epigenetic regulation. Although transcriptional regulation governing hepatocyte differentiation has been extensively studied, how metabolic remodeling interacts with epigenetic regulation during hepatocyte maturation remains poorly understood. Using a human embryonic stem cell-derived hepatocyte organoid differentiation model, we identified JMJD3 as a critical regulator of hepatocyte maturation through metabolic-epigenetic coupling. Mechanistically, JMJD3 activated the fatty acid β-oxidation (FAO) enzyme HADH by removing repressive H3K27me3 marks at its locus, thereby promoting FAO activity during hepatocyte maturation. Enhanced FAO increased acetyl-CoA production, which subsequently promoted EP300-mediated H3K27ac deposition at hepatocyte maturation-associated genes. Functional inhibition of JMJD3, HADH, or FAO impaired hepatocyte maturation, resulting in lipid droplet accumulation and reduced expression of hepatocyte maturation markers. Conversely, restoration of acetyl-CoA partially rescued these maturation defects, supporting a functional link between FAO-dependent metabolism and histone acetylation. Collectively, our findings establish a JMJD3-HADH-FAO-acetyl-CoA regulatory axis that coordinates metabolic remodeling and epigenetic regulation during hepatocyte maturation.
Metabolic dysfunction-associated steatohepatitis (MASH) involves pathological crosstalk within the gut-liver axis, in which intestinal barrier dysfunction facilitates the translocation of microbial and dietary products and aggravates hepatic inflammation and fibrosis. Although phosphodiesterase 3B (PDE3B) is known to regulate metabolic and inflammatory processes, its role in gut-liver communication remains unclear. Here, we demonstrate that genetic ablation of PDE3B and pharmacological PDE3 inhibition using cilostamide significantly improve hepatic and intestinal features of MASH in diet-induced mouse models. Specifically, PDE3B loss and pharmacological PDE3 inhibition preserve intestinal barrier integrity by restoring tight junction protein expression and reducing intestinal permeability, accompanied by attenuated hepatic inflammatory and fibrotic responses. Mechanistically, loss of PDE3B suppresses nuclear factor-κB-driven inflammatory signaling through activation of a cAMP-protein kinase A-dependent pathway, as reflected by increased phosphorylation of cAMP response element-binding protein. Notably, ileal PDE3B protein declines earlier than hepatic PDE3B during MASH progression, supporting early intestinal engagement during diet-induced metabolic stress. These findings support PDE3B/PDE3 signaling as a therapeutically tractable multi-organ regulatory node of gut-liver axis pathology in MASH and identify pharmacological PDE3 inhibition as a viable strategy to mitigate hepatic injury while preserving intestinal barrier-associated function.
Abstract T cell exhaustion arises during chronic antigen stimulation and represents a major barrier to effective anti-tumour immunity. Rather than a uniform dysfunctional state, exhaustion is increasingly understood as a structured differentiation landscape that progresses from stem-like progenitor exhausted T cells to terminally exhausted T cells. Stem-like progenitor exhausted T cells retain self-renewal capacity and partial effector function, whereas terminally exhausted T cells exhibit epigenetically fixed dysfunction and limited cytokine production. Within the tumour microenvironment, persistent antigen stimulation, together with metabolic stressors such as hypoxia and nutrient deprivation, accelerates this differentiation trajectory, thereby constraining protective immunity. In this review, we conceptualize T cell exhaustion as a dynamic continuum shaped by both differentiation states and microenvironmental niches. We outline an integrative framework to define exhaustion by combining antigen experience, cellular phenotype, functional capacity, epigenetic fixation and spatial context. Viewing immunotherapies through this multidimensional framework highlights the notion that durable therapeutic responses depend on preserving stem-like progenitor exhausted T cells within supportive niches and preventing their terminal differentiation. Understanding how these cellular states are maintained or disrupted within the tumour microenvironment will provide new opportunities for designing therapies that sustain protective T cell immunity in cancer.
