Cell Death and Differentiation最新文献

{"title":"SETD7 depletion enhances white adipose browning and ameliorates metabolic disorders in obese mice.","authors":"Chenxi Xiao, Yajie Hu, Jiayao Liu, Jialin Zhao, Jie Xu, Honghong Chen, Qiuyuan Huang, Wugui Chen, Jun Chang, Xinhua Liu, Chengshou Lin","doi":"10.1038/s41418-026-01790-x","DOIUrl":"https://doi.org/10.1038/s41418-026-01790-x","url":null,"abstract":"<p><p>Obesity, a major global health challenge associated with metabolic and cardiovascular disorders, has drawn increasing attention to the therapeutic potential of white adipose tissue (WAT) browning. Although the lysine methyltransferase SETD7 has been implicated in various cardiovascular and metabolic diseases, its role in adipose thermogenesis remains unclear. Here, we reported that SETD7 was upregulated in inguinal WAT (iWAT) of obese mice and was primarily localized to mature adipocytes. Setd7 knockdown (Setd7^⁺/⁻) mice exhibited enhanced thermogenic gene expression and iWAT browning upon cold exposure or β3-adrenergic stimulation, whereas thermogenic activity in brown adipose tissue (BAT) remained largely unaffected. In vitro, SETD7 knockdown did not alter adipogenesis but potently augmented thermogenic capacity in beige adipocytes, while SETD7 overexpression exerted the opposite effect. Mechanistically, RNA-Seq analysis revealed that SETD7 deficiency upregulated Adcy7 transcription, leading to increased Sirt1 levels and enhanced Creb1 phosphorylation, thereby activating the thermogenic program. Notably, Setd7^⁺/^- mice resisted high-fat diet (HFD)-induced obesity, exhibiting reduced weight gain, elevated energy expenditure, and improved metabolic health. Together, these findings identify SETD7 as a negative regulator of iWAT thermogenesis and suggest that targeting SETD7 may represent a promising strategy for combating obesity.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell engulfment defines spatially distinct competitive metabolic niches associated with clinical outcomes in colorectal cancer.","authors":"Emir Bozkurt, Batuhan Kisakol, Heiko Dussmann, Federico Lucantoni, Anna Sturrock, Mohammadreza Azimi, Sanghee Cho, Elizabeth McDonough, Joana Fay, Tony O'Grady, John P Burke, Niamh McCawley, Deborah A McNamara, Daniel B Longley, Fiona Ginty, Jochen H M Prehn","doi":"10.1038/s41418-026-01801-x","DOIUrl":"10.1038/s41418-026-01801-x","url":null,"abstract":"<p><p>Cell competition is an emerging mechanism in which mammalian tissues maintain homeostasis by eliminating less fit (loser) cells through direct interactions with fitter (winner) neighbouring cells. In cancer, these competitive interactions may drive tumour evolution; however, spatial organisation and clinical relevance of these events remain poorly understood. One mechanism by which winner cells eliminate loser cells is engulfment, resulting in cell-in-cell (CIC) formation. Although CICs have been observed in many tumour types for over a century, their cellular composition, spatial context, interactions with the tumour microenvironment, and biological significance in human cancers remain unclear. Here, we systematically characterised the cellular identity and functional states of CICs in situ, examined their spatial interactions within the tumour microenvironment, and assessed their clinical relevance using spatially resolved single-cell data from a large cohort of colorectal cancer patients. We demonstrated that CICs occurred predominantly between cancer cells but also involved cancer stem cell (CSC)-like populations and cytotoxic T cells. Engulfed (inner) cancer and CSC-like cells displayed molecular features consistent with a loser-cell phenotype, including increased apoptosis and reduced proliferation, whereas outer cancer cells exhibited winner-cell features such as upregulated glycolysis. Live-cell time-lapse experiments demonstrated that glucose accumulated in inner cells during lysosomal degradation following cell engulfment. Spatial analysis further revealed distinct CIC neighbourhoods, which we defined based on proximity to engulfment events. Cells within these regions, particularly CSC-like cells and cytotoxic T cells, exhibited increased metabolic stress, suggesting local competition for nutrients. Importantly, the presence of cytotoxic T cells within CIC neighbourhoods and spatial co-occurrence between cancer cells and CSC-like populations were associated with improved patient outcomes. Together, our findings demonstrate that cell engulfment defines spatially organised competitive niches and may reflect cell competition within complex tumour microenvironments.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.","authors":"Yiming Wang, Zhuoran Ma, Zongjie Jin, Liang Kou, Nian Xiong, Tao Wang, Yun Xia","doi":"10.1038/s41418-026-01800-y","DOIUrl":"https://doi.org/10.1038/s41418-026-01800-y","url":null,"abstract":"<p><p>Emerging evidence suggests that microglia exhibit dual regulatory roles in the pathogenesis of Parkinson's disease (PD); however, their precise function in α-synuclein clearance remains incompletely understood. Here, we provide compelling evidence that α-synuclein preformed fibrils (α-syn PFF) impair lysosomal acidification in microglia, leading to defective autophagic flux and disrupted α-syn degradation. This dysfunction further promotes the secretion of microglial extracellular vesicles (EVs), exacerbating disease pathology. Mechanistic investigations uncover that α-syn PFF directly interacts with ATP6V0C, a pivotal V0 subunit of V-ATPase. This interaction sterically hinders V0-V1 domain assembly, disrupting proton pump complex formation and reducing ATP6V0C expression. Functionally, ATP6V0C overexpression rescues lysosomal acidification deficits and facilitates α-syn degradation in vitro, while in vivo, ATP6V0C overexpression alleviates neurotoxicity and reduces phosphorylated α-syn aggregation in α-syn PFF mouse models. Further investigation identifies the PI3K-AKT-mTOR-TFEB pathway as a key regulatory axis of ATP6V0C-mediated lysosomal acidification in microglia. Notably, both TFEB activation and mTOR inhibition restore lysosomal acidity and upregulate ATP6V0C expression, thereby enhancing α-syn clearance. These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SUMOylation-stabilized G6PD orchestrates metabolic rewiring for oxidative stress survival and chemoresistance in HCC via a PKCδ-phosphorylation trigger","authors":"Hongliang Luo, Fenna Zhang, Yingping Li, Rui Tong, Chengchang Gao, Yueqi Wen, Xueli Bian","doi":"10.1038/s41418-026-01802-w","DOIUrl":"https://doi.org/10.1038/s41418-026-01802-w","url":null,"abstract":"The adaptive mechanisms enabling cancer cells to withstand oxidative stress through metabolic rewiring remain poorly defined. Here, we decipher a redox-operated phosphorylation-SUMOylation relay that dynamically regulates glucose-6-phosphate dehydrogenase (G6PD) to drive hepatocellular carcinoma (HCC) progression. Oxidative stress activates protein kinase C delta (PKCδ), which phosphorylates G6PD at threonine 236 (T236), creating a steric barrier that displaces the deSUMOylase SENP1 and licenses K238 SUMOylation. This dual post-translational modification orchestrates G6PD stabilization through impaired TRIM21-mediated ubiquitination and catalytic activation via dimeric structural reorganization. Functionally, stabilized G6PD amplifies pentose phosphate pathway flux, sustaining NADPH-dependent redox balance and ribose-5-phosphate-fueled nucleotide biosynthesis to promote HCC survival under oxidative duress. Genetic disruption of K238 SUMOylation or pharmacological PKCδ inhibition synergistically enhances cisplatin efficacy by overcoming chemoresistance in preclinical models. Clinically, coordinated upregulation of G6PD and phospho-T236 correlates with aggressive HCC phenotypes and predicts poor patient outcomes. Our study identifies G6PD post-translational control as a potential metabolic vulnerability and suggests that targeted disruption of this axis may represent a promising approach to subvert redox adaptation in HCC.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Pax6 sumoylation suppresses the tumorigenicity of pancreatic cancer cells.","authors":"Yuan Xiao, Jing-Miao Wang, Yu-Yan Shan, Jia-Ling Fu, Mi Deng, Yan Wang, Jian-Ping Zhang, Shu-Yu Zheng, Ming Zou, Yu-Wen Gan, Xing-Miao Liang, Xue-Bin Hu, Lan Zhang, David Wan-Cheng Li","doi":"10.1038/s41418-026-01789-4","DOIUrl":"https://doi.org/10.1038/s41418-026-01789-4","url":null,"abstract":"<p><p>Pax6 is a critical transcription factor that regulates the development of multiple tissues, including the nervous system, ocular tissues, and pancreas. We have previously demonstrated that p32 Pax6 function is substantially regulated by protein sumoylation mediated through SUMO1 at the primary residue, Lys-91, and to a less degree at Lys-110 of the p32 Pax6 (K91/110) (Yan et al., 2010, PNAS). To further investigate the function of Pax6 sumoylation, we established stable PANC-1 pancreatic cancer cell line overexpressing p32 Pax6. Injection of these cells into immune-deficient mice promoted much enhanced tumor development than both parental and vector-transfected cells. Inhibition of Pax6 sumoylation with the sumoylation inhibitor ML-792 markedly suppressed tumor growth. Moreover, ML-792 treatment of the developed tumors also significantly suppressed tumor growth. To further study the underlying mechanisms, we generated the PANC-1 cell lines expressing K91/110R-p32 Pax6 and demonstrated that inhibition of Pax6 sumoylation through K91/110R mutations also suppressed its ability to promote tumor development in nude mice. Furthermore, K91R-p32 Pax6 knock-in mice exhibited changed cell populations in adult pancreas tissue and altered transcriptomes in the pancreas in vivo, which resembled the changes observed in PANC-1 cells expressing K91/110R-p32 Pax6 ex vivo. RNA sequencing, gel mobility shifting, chromatin immunoprecipitation, and Cut & Run assays revealed that the CXXC finger protein 4 (CXXC4) is the major downstream target directly regulated by Pax6. Silencing of CXXC4 in PANC-1 and CAPAN-1 cells expressing p32 Pax6 inhibited Pax6-induced tumor development in nude mice, exhibiting the phenotype similar to that observed in PANC-1 and CAPAN-1 cells expressing K91/110R-p32 Pax6. Together, our results demonstrated that inhibition of Pax6 sumoylation suppresses tumorigenicity of PANC-1 and CAPAN-1 pancreatic cancer cells through CXXC4. Our findings suggest that targeting Pax6 sumoylation may serve as a potential therapeutic target for pancreatic cancer treatment.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging roles of alternative splicing in modulating tumor immune responses and immunotherapies.","authors":"Xinyu He, Dengyun Zhao, Yubing Zhou, Yanan Jiang, Zigang Dong, Kangdong Liu","doi":"10.1038/s41418-026-01792-9","DOIUrl":"https://doi.org/10.1038/s41418-026-01792-9","url":null,"abstract":"<p><p>Alternative splicing is a fundamental mechanism that expands transcriptomic and proteomic diversity and contributes to multiple biological processes, including immune regulation. Increasing evidence shows that dysregulated alternative splicing influences tumor immunogenicity, the immune landscape of the tumor microenvironment, and responses to cancer immunotherapy. Alternative splicing can alter the expression and peptide repertoire of tumor antigens, modulate major histocompatibility complex-mediated antigen presentation, and generate immunomodulatory isoforms that promote immune evasion. In addition, cell type-specific splicing programs regulate the phenotypes and functions of intratumoral immune and stromal cells, including T cells, antigen-presenting cells, myeloid cells, and fibroblasts. Splicing signatures and isoform-level alterations are also associated with clinical responses to immunotherapy, particularly immune checkpoint blockade. A better understanding of splicing dysregulation in tumor immunity may improve biomarker development, patient stratification, and therapeutic targeting of aberrant RNA processing. Overall, alternative splicing is an important regulator of tumor-immune interactions and a potential target in cancer immunotherapy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efferocytosis enhances macrophage pro-angiogenic functions for bone marrow regeneration","authors":"Yue Li, Zuo Zhang, Ran Yao, Xiying Jin, Zan Yong, Xuguang Song, Cai Sun, Zhengqing Xu, Yujin Huang, Wen Ju, Yuan He, Jianlin Qiao, Lingyu Zeng","doi":"10.1038/s41418-026-01788-5","DOIUrl":"https://doi.org/10.1038/s41418-026-01788-5","url":null,"abstract":"Myeloablative treatments before bone marrow (BM) transplantation severely disrupt the microvasculature of the BM, and its regeneration precedes and supports hematopoietic regeneration after BM transplantation. Thus, the identification of factors that regulate BM vascular regeneration after an injury could offer a significant therapeutic opportunity to improve hematopoietic regeneration. After myeloablation, the BM cavity is filled with various dying cell-derived products. Here, we show that after transplantation, dying cell-derived products educate macrophages into a proangiogenic state and enhance vascular regeneration in the BM. Mechanistically, dying cell-derived sphingosine-1-phosphate (S1P) primes hypoxia-inducible factor-1α (HIF-1α) gene expression in macrophages. Importantly, our results revealed that the degradation of apoptotic bodies (ApoBDs) elevates intracellular cholesterol levels and activates their sensor, liver X receptor α (LXRα), in macrophages. Activated LXRα physically binds to the HIF-1α protein and inhibits its ubiquitylation, further potentiating VEGFA expression in macrophages. In vivo studies using transgenic mouse models and liposome-mediated delivery confirm that the LXRα/HIF-1α axis is required for macrophage-driven vascular repair following transplantation. These data not only uncover a new role for macrophages in BM vascular regeneration, but also provide novel evidence demonstrating the unexpected beneficial effect of efferocytosis in eliciting the pro-healing functions of macrophages in the context of injury.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"21 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148305473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZFP36L1 and ZFP36L2 cooperatively regulate thymic epithelial cell function to prevent early-onset thymic involution","authors":"Pedro Ferreirinha, Pedro M. Rodrigues, Francisco Sobral, Bruno Cavadas, Rúben G. R. Pinheiro, Ana Mafalda Rocha, Yousuke Takahama, Martin Turner, Nuno L. Alves","doi":"10.1038/s41418-026-01793-8","DOIUrl":"https://doi.org/10.1038/s41418-026-01793-8","url":null,"abstract":"The thymus generates immunocompetent T cells, but its function declines with age. Thymic activity relies on proper differentiation of thymic epithelial cells (TECs), which establish unique niches for T-cell development. However, the molecular mechanisms governing the differentiation of functional cortical (c) and medullary (m) TEC subsets from common progenitors remain poorly understood. Using dual conditional knockout (dcKO) and lineage-tracing mouse models, we demonstrated that RNA-binding proteins ZFP36L1 and ZFP36L2 cooperatively maintain a functional TEC microenvironment. TEC-specific deletion of <jats:italic>Zfp36l1</jats:italic> and <jats:italic>Zfp36l2</jats:italic> in dcKO mouse models led to early-onset thymic hypoplasia and a marked reduction in TEC and thymocyte numbers. Mechanistically, single-cell transcriptomics revealed significant alterations in the composition and transcriptional programs of cTECs, mTECs, and thymic mimetic cells, linking <jats:italic>Zfp36l1</jats:italic> and <jats:italic>Zfp36l2</jats:italic> deficiency to a widespread increase in metabolic gene dysregulation in adult dcKO TECs. The erosion of the TEC compartment and the accumulation of age-associated TECs suggested impaired differentiation of mature lineages from their progenitors. Concordantly, fate-mapping analysis revealed that dual deficiency in <jats:italic>Zfp36l1</jats:italic> and <jats:italic>Zfp36l2</jats:italic> disrupted the canonical developmental trajectory from β5t-expressing TEC progenitors into mature TECs. Our findings uncover a previously unappreciated layer of post-transcriptional regulation in TEC biology, identifying a cooperative role for ZFP36L1 and ZFP36L2 in orchestrating TEC differentiation to sustain thymic function and prevent premature involution.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"32 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148305475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP21-mediated deubiquitylation stimulates NuMA recruitment to the cell cortex to promote mitotic spindle orientation","authors":"Mingzheng Hu, Huixian Ma, Runa Wang, Zhenqi Yu, Jinqiong Wang, Lin Li, Difei Wang, Hanxiao Yin, Mulin Yang, Feifei Qi, Ying Shan, Huijie Zhao, Jinmin Gao, Dengwen Li, Min Liu, Jun Zhou","doi":"10.1038/s41418-026-01786-7","DOIUrl":"https://doi.org/10.1038/s41418-026-01786-7","url":null,"abstract":"Proper orientation of the mitotic spindle is critical for a wide range of biological processes. However, the molecular mechanisms that regulate the formation of the spindle orientation machinery remain incompletely understood. In this study, we identify an essential role for ubiquitin-specific peptidase 21 (USP21)-mediated deubiquitylation in the control of spindle orientation. Histological analyses of Usp21 knockout mice revealed multiple epithelial abnormalities, including delayed corneal epithelial stratification, dilated renal tubules, and impaired skin wound healing. These defects were attributable to spindle misorientation in corresponding epithelial tissues. In vitro studies further confirmed that USP21 deficiency disrupts spindle orientation in cultured cells. Mechanistically, USP21 interacts with nuclear mitotic apparatus protein (NuMA) and removes the lysine 63-linked ubiquitylation of NuMA at lysine 1330 and lysine 1335. The deubiquitylation of NuMA triggers its interaction with Leu-Gly-Asn repeat-enriched protein (LGN), thereby recruiting NuMA to the cell cortex to form the spindle orientation machinery. Collectively, these findings uncover a previously unrecognized role for USP21 in spindle orientation and underscore its importance in epithelial development and homeostasis through the deubiquitylation of NuMA.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"156 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148305476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fas acts as a T cell co-stimulatory receptor via both death domain-independent and -dependent mechanisms","authors":"Giorgia Miloro, Laurent Gagnoux-Palacios, Sébastien Huault, Agnès Loubat, Anthony Formisano, Xiao-Jun Guo, Viktória Jenei, Gábor Koncz, Hai-Tao He, Anne-Odile Hueber, Aurélie Rossin","doi":"10.1038/s41418-026-01782-x","DOIUrl":"https://doi.org/10.1038/s41418-026-01782-x","url":null,"abstract":"T cell responses are regulated by co-stimulatory and inhibitory signalling pathways, driven by receptors and their ligands designated as immune checkpoints. These receptors belong either to the immunoglobulin superfamily or the tumour necrosis factor receptor (TNFR) superfamily. Despite their crucial role in enhancing T effector cell activity, the molecular mechanisms triggered by TNFR co-stimulatory receptors, particularly their integration into the T cell receptor (TCR) signalling network, remain incompletely characterised. The receptor Fas is classically recognised as the prototypical TNFR death receptor due to the presence of an intracellular death domain (DD). While best known for its ability to trigger cell death, Fas has also been involved in non-death functions, including T cell co-stimulation. Despite its key role in dictating T cell fate, the molecular mechanisms underlying its TCR co-stimulatory receptor function have not been fully elucidated. We show here that Fas constitutively concentrates in plasma membrane domains at the immune synapse where it can be activated by antigen-presenting cell (APC) membrane-anchored FasL. This proximity to the TCR signalling molecules allows Fas, in a DD-independent manner, to lower the TCR activation threshold thereby enhancing the number of activated cells. Additionally, Fas triggers a DD-dependent signalling cascade composed of FADD, caspase-8 and RIPK1, ultimately leading to TAK1 activation. TAK1 in turn initiates gene-activating signalling pathways essential for an optimal Fas co-stimulatory response. Moreover, we identified the catalytic activity of caspase-8 as a tipping point in Fas signalling during TCR co-stimulation. Indeed, inhibiting caspase 8 not only prevents cell death but also promotes T cell co-stimulation by favouring RIPK1-dependent signalling. Altogether, our findings reveal a complex mechanism by which Fas integrates at multiple levels of the TCR spatial organization and signalling network, synergising with TCR signalling to achieve full T cell activation.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"20 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148290411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}