Pub Date : 2026-01-08DOI: 10.1038/s41556-025-01842-3
He Ren, Leina Ma, Xiaoming Jiang, Zhimin Lu
Lactate acts as a metabolic fuel, a signalling molecule and a protein modifier. A study reveals that in glioblastoma, a lactate-mediated metabolic crosstalk between tumour-associated macrophages and glioblastoma stem-like cells enhances DNA repair, promotes stemness, drives immune evasion and accelerates tumour growth.
{"title":"Immune evasion by macrophage-derived lactate","authors":"He Ren, Leina Ma, Xiaoming Jiang, Zhimin Lu","doi":"10.1038/s41556-025-01842-3","DOIUrl":"10.1038/s41556-025-01842-3","url":null,"abstract":"Lactate acts as a metabolic fuel, a signalling molecule and a protein modifier. A study reveals that in glioblastoma, a lactate-mediated metabolic crosstalk between tumour-associated macrophages and glioblastoma stem-like cells enhances DNA repair, promotes stemness, drives immune evasion and accelerates tumour growth.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"220-221"},"PeriodicalIF":19.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934338","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}
Pub Date : 2026-01-08DOI: 10.1038/s41556-025-01848-x
We present SpaHDmap, a deep learning framework that integrates histology images with spatial transcriptomic data to derive high-resolution and interpretable spatial metagenes. We demonstrate that SpaHDmap effectively generates fine-grained spatial metagenes, reveals refined spatial structures and enables joint analysis of multiple samples across different experimental conditions.
{"title":"Revealing high-resolution spatial metagenes from spatial transcriptomics","authors":"","doi":"10.1038/s41556-025-01848-x","DOIUrl":"10.1038/s41556-025-01848-x","url":null,"abstract":"We present SpaHDmap, a deep learning framework that integrates histology images with spatial transcriptomic data to derive high-resolution and interpretable spatial metagenes. We demonstrate that SpaHDmap effectively generates fine-grained spatial metagenes, reveals refined spatial structures and enables joint analysis of multiple samples across different experimental conditions.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"224-225"},"PeriodicalIF":19.1,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934258","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}
Pub Date : 2026-01-07DOI: 10.1038/s41556-025-01844-1
Ruben van der Lugt, Jacqueline J. L. Jacobs
Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function. This Review presents an updated view on telomeric chromatin as a dynamic structure with a specialized histone organization and discusses the mechanisms of its regulation by cis-acting subtelomeric elements, as well as their relevance in disease.
{"title":"Structural organization and function of telomeric chromatin","authors":"Ruben van der Lugt, Jacqueline J. L. Jacobs","doi":"10.1038/s41556-025-01844-1","DOIUrl":"10.1038/s41556-025-01844-1","url":null,"abstract":"Telomeres were originally classified as constitutive heterochromatin, an inert chromatin state characteristic of repetitive regions. However, this view has been increasingly challenged by analyses of the epigenetic signature and molecular behaviour of human telomeric chromatin. Recent structural and genetic studies further highlight the distinctive and dynamic nature of the telomeric architecture. Here we present an updated perspective on telomeric chromatin, focusing on the unique features that set telomeres apart from other genomic regions and that equip them to address the specific challenges at chromosome ends. In addition, we discuss how alterations in telomeric chromatin influence stem cells, inherited diseases and cancer, demonstrating how telomere architecture governs both its integrity and function. This Review presents an updated view on telomeric chromatin as a dynamic structure with a specialized histone organization and discusses the mechanisms of its regulation by cis-acting subtelomeric elements, as well as their relevance in disease.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"226-239"},"PeriodicalIF":19.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907947","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}
Pub Date : 2026-01-07DOI: 10.1038/s41556-025-01853-0
Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley
Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR–Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability. Yashinskie, Zhu and colleagues show that p53 activation triggers increased synthesis and accumulation of phospholipids, with enhanced activation of autophagy and lysosomal catabolism programmes and increased reliance on lipid headgroup recycling.
{"title":"p53 increases phospholipid headgroup scavenging in senescence","authors":"Jossie J. Yashinskie, Xianbing Zhu, Grace H. McGregor, Karl A. Wessendorf-Rodriguez, Katrina Paras, Julia S. Brunner, Benjamin T. Jackson, Abigail Xie, Richard Koche, Christian M. Metallo, Lydia W. S. Finley","doi":"10.1038/s41556-025-01853-0","DOIUrl":"10.1038/s41556-025-01853-0","url":null,"abstract":"Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR–Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability. Yashinskie, Zhu and colleagues show that p53 activation triggers increased synthesis and accumulation of phospholipids, with enhanced activation of autophagy and lysosomal catabolism programmes and increased reliance on lipid headgroup recycling.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"296-306"},"PeriodicalIF":19.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01853-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC. Wang, Chu, Chen, Wei and colleagues discover a subset of tumour-associated macrophages expressing SLC2A1 whose spatial proximity to CD8+ T cells drives resistance to anti-PD-L1 treatment in non-small-cell lung cancer.
{"title":"SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer","authors":"Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, Bo Zhu, Qian Chu","doi":"10.1038/s41556-025-01840-5","DOIUrl":"10.1038/s41556-025-01840-5","url":null,"abstract":"Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC. Wang, Chu, Chen, Wei and colleagues discover a subset of tumour-associated macrophages expressing SLC2A1 whose spatial proximity to CD8+ T cells drives resistance to anti-PD-L1 treatment in non-small-cell lung cancer.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"338-348"},"PeriodicalIF":19.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01840-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1038/s41556-025-01785-9
Dario Rizzotto, Christian Zierhut, Andreas Villunger
Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations. Rizzotto et al. discuss the causes and consequences of deregulated mitosis that allow cells arrested in mitosis to escape to the next interphase, where they can initiate inflammatory signalling or undergo cell death, with therapeutic implications.
{"title":"Mitotic errors as triggers of cell death and inflammation","authors":"Dario Rizzotto, Christian Zierhut, Andreas Villunger","doi":"10.1038/s41556-025-01785-9","DOIUrl":"10.1038/s41556-025-01785-9","url":null,"abstract":"Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations. Rizzotto et al. discuss the causes and consequences of deregulated mitosis that allow cells arrested in mitosis to escape to the next interphase, where they can initiate inflammatory signalling or undergo cell death, with therapeutic implications.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"21-34"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902710","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}
Pub Date : 2026-01-06DOI: 10.1038/s41556-025-01838-z
Junjie Tang, Zihao Chen, Kun Qian, Siyuan Huang, Yang He, Shenyi Yin, Xinyu He, Buqing Ye, Yan Zhuang, Hongxue Meng, Jianzhong Jeff Xi, Ruibin Xi
Spatial transcriptomics (ST) technologies revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit considerable noise and sparsity, posing substantial challenges in deciphering subtle spatial structures and underlying biological activities. Here we introduce ‘spatial high-definition embedding mapping’ (SpaHDmap), an interpretable dimension reduction framework that enhances spatial resolution by integrating ST gene expression with high-resolution histology images. SpaHDmap incorporates non-negative matrix factorization into a deep learning framework, enabling the identification of high-resolution spatial metagenes (embeddings). Furthermore, SpaHDmap can simultaneously analyse multiple samples and is compatible with various types of histology images. Extensive evaluations on synthetic, public and newly sequenced ST datasets from various technologies and tissue types demonstrate that SpaHDmap can effectively produce high-resolution spatial metagenes, and detect refined spatial structures. SpaHDmap represents a powerful approach for integrating ST data and histology images, offering deeper insights into complex tissue structures and functions. Tang, Chen, Qian et al. present a multimodal, interpretable dimension reduction framework called SpaHDmap, which leverages histology images and enhances the resolution of spatial transcriptomics, thus enabling the dissection of complex tissue structures.
{"title":"The interpretable multimodal dimension reduction framework SpaHDmap enhances resolution in spatial transcriptomics","authors":"Junjie Tang, Zihao Chen, Kun Qian, Siyuan Huang, Yang He, Shenyi Yin, Xinyu He, Buqing Ye, Yan Zhuang, Hongxue Meng, Jianzhong Jeff Xi, Ruibin Xi","doi":"10.1038/s41556-025-01838-z","DOIUrl":"10.1038/s41556-025-01838-z","url":null,"abstract":"Spatial transcriptomics (ST) technologies revolutionized tissue architecture studies by capturing gene expression with spatial context. However, high-dimensional ST data often have limited spatial resolution and exhibit considerable noise and sparsity, posing substantial challenges in deciphering subtle spatial structures and underlying biological activities. Here we introduce ‘spatial high-definition embedding mapping’ (SpaHDmap), an interpretable dimension reduction framework that enhances spatial resolution by integrating ST gene expression with high-resolution histology images. SpaHDmap incorporates non-negative matrix factorization into a deep learning framework, enabling the identification of high-resolution spatial metagenes (embeddings). Furthermore, SpaHDmap can simultaneously analyse multiple samples and is compatible with various types of histology images. Extensive evaluations on synthetic, public and newly sequenced ST datasets from various technologies and tissue types demonstrate that SpaHDmap can effectively produce high-resolution spatial metagenes, and detect refined spatial structures. SpaHDmap represents a powerful approach for integrating ST data and histology images, offering deeper insights into complex tissue structures and functions. Tang, Chen, Qian et al. present a multimodal, interpretable dimension reduction framework called SpaHDmap, which leverages histology images and enhances the resolution of spatial transcriptomics, thus enabling the dissection of complex tissue structures.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"363-377"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41556-025-01838-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1038/s41556-025-01784-w
Colin Richard Gliech, Andrew Jon Holland
Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity. This Perspective discusses our current understanding of the timing mechanisms that couple mitotic duration to cell fate, including emerging evidence for the existence of mitotic clocks that enable cells to preserve genomic integrity.
{"title":"Biological clocks keep a watch on mitosis","authors":"Colin Richard Gliech, Andrew Jon Holland","doi":"10.1038/s41556-025-01784-w","DOIUrl":"10.1038/s41556-025-01784-w","url":null,"abstract":"Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity. This Perspective discusses our current understanding of the timing mechanisms that couple mitotic duration to cell fate, including emerging evidence for the existence of mitotic clocks that enable cells to preserve genomic integrity.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"13-20"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902709","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}
Pub Date : 2026-01-06DOI: 10.1038/s41556-025-01839-y
Daqi Li, Gaoyuan Cui, Kailin Yang, Chenfei Lu, Yuhan Jiang, Le Zhang, Qiulian Wu, Deobrat Dixit, Zhe Zhu, Ryan C. Gimple, Danling Gu, Jiancheng Gao, Qiankun Lin, Hang Yu, Zhumei Shi, Yun Chen, Qianghu Wang, Guangfu Jin, Fan Lin, Junfei Shao, Qigang Zhou, Chong Liu, Chaojun Li, Yongping You, Nu Zhang, Junxia Zhang, Xu Qian, Qian Zhang, Jeremy N. Rich, Xiuxing Wang
Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4–MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS–STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM. Li, Cui, Yang, Lu, Jiang, Zhang and colleagues identify a lactate transport mechanism from tumour-associated macrophages that regulates DNA repair and immune cell infiltration, which could be targeted to enhance immunotherapy efficacy in glioblastoma models.
{"title":"Inhibiting macrophage-derived lactate transport restores cGAS–STING signalling and enhances antitumour immunity in glioblastoma","authors":"Daqi Li, Gaoyuan Cui, Kailin Yang, Chenfei Lu, Yuhan Jiang, Le Zhang, Qiulian Wu, Deobrat Dixit, Zhe Zhu, Ryan C. Gimple, Danling Gu, Jiancheng Gao, Qiankun Lin, Hang Yu, Zhumei Shi, Yun Chen, Qianghu Wang, Guangfu Jin, Fan Lin, Junfei Shao, Qigang Zhou, Chong Liu, Chaojun Li, Yongping You, Nu Zhang, Junxia Zhang, Xu Qian, Qian Zhang, Jeremy N. Rich, Xiuxing Wang","doi":"10.1038/s41556-025-01839-y","DOIUrl":"10.1038/s41556-025-01839-y","url":null,"abstract":"Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4–MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS–STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM. Li, Cui, Yang, Lu, Jiang, Zhang and colleagues identify a lactate transport mechanism from tumour-associated macrophages that regulates DNA repair and immune cell infiltration, which could be targeted to enhance immunotherapy efficacy in glioblastoma models.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 2","pages":"349-362"},"PeriodicalIF":19.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902714","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}
Pub Date : 2026-01-05DOI: 10.1038/s41556-025-01841-4
Sarah May Russell, Mirren Charnley
The discovery that CD8+ T cells divide asymmetrically has generated considerable speculation regarding how such divisions regulate the fate of these cells. Excitingly, a recent study links the inheritance of a fate determinant to divergence in CD8+ T cell fate among the daughters of an asymmetric division.
{"title":"Mitochondrial asymmetry shifts T cell fate","authors":"Sarah May Russell, Mirren Charnley","doi":"10.1038/s41556-025-01841-4","DOIUrl":"10.1038/s41556-025-01841-4","url":null,"abstract":"The discovery that CD8+ T cells divide asymmetrically has generated considerable speculation regarding how such divisions regulate the fate of these cells. Excitingly, a recent study links the inheritance of a fate determinant to divergence in CD8+ T cell fate among the daughters of an asymmetric division.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"28 1","pages":"2-3"},"PeriodicalIF":19.1,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902713","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}
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