Cell Death Discovery最新文献

{"title":"Doxorubicin promotes the production of inflammatory cytokines in tumor-associated macrophages through activating lactate dehydrogenase A.","authors":"Bin Liu, Wei Yang, Shuo Feng, Xingning Jiang, Jingfan Lu, Fei Wang, Yaowen Hu, Yanhao Liu, Haifeng Ma, Ting Sun","doi":"10.1038/s41420-026-03014-0","DOIUrl":"https://doi.org/10.1038/s41420-026-03014-0","url":null,"abstract":"<p><p>Glioblastoma (GBM) presents a significant challenge because of its immunosuppressive microenvironment. The standard treatment protocol, including surgery, radiotherapy, and temozolomide, has been unable to alleviate immunosuppression. Doxorubicin chemotherapy induces immunogenic cell death in cancer cells, reshaping an immune-activated microenvironment. Here, we investigated the mechanism of immune activation induced by doxorubicin in tumor-associated macrophages (TAMs). Radiotherapy and temozolomide plus doxorubicin inhibited tumor growth and reduced the levels of immunosuppressive markers. Mechanically, doxorubicin promotes the production of lactate through activating lactate dehydrogenase A (LDHA) to upregulate the transcription of inflammatory cytokines. Our study confirmed a new mechanism by which doxorubicin remodels the tumor microenvironment by promoting the glycolytic process and lactic acid production, suggesting that combining radiotherapy and temozolomide with doxorubicin chemotherapy may be a potential strategy for GBM treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Periplogenin attenuates LPS-mediated inflammatory osteolysis through the suppression of osteoclastogenesis via reducing the NF-κB and MAPK signaling pathways.","authors":"Kai Gan, Haoyu Lian, Tao Yang, Jian Huang, Junchun Chen, Yuangang Su, Jinmin Zhao, Jiake Xu, Qian Liu","doi":"10.1038/s41420-026-03007-z","DOIUrl":"10.1038/s41420-026-03007-z","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13035846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCR4, CXCR7 and PBRM1 are responsible for everolimus and cabozantinib resistance in human renal cancer cells.","authors":"Federica Auletta, Caterina Ieranò, Dario Guido Di Febbraro, Anna Maria Bello, Giuseppina Rea, Maria Napolitano, Francesca Galdiero, Giuseppe Guardascione, Anna Maria Trotta, Sara Santagata, Cinzia Vetrei, Gaetana Di Maiolo, Daniela Russo, Anna Spina, Crescenzo D'Alterio, Luigi Portella, Serena Ascrizzi, Giovanni Luca Scaglione, Pierfrancesco Tassone, Maria Teresa Di Martino, Stefania Scala","doi":"10.1038/s41420-026-03026-w","DOIUrl":"10.1038/s41420-026-03026-w","url":null,"abstract":"<p><p>The mTOR inhibitor everolimus (RAD001), previously used in first-line treatment of metastatic renal cancer (mRCC), is currently reserved for the following lines of therapy. However, many patients eventually develop resistance to RAD001. To shed new light on the mechanism of RAD001 resistance, A498 cells resistant to 1-5-10 µM of RAD001 were developed (A498-RAD 1-5-10). A498-RAD-resistant cells overexpressed the chromatin remodeling factor PBRM1 and mTOR and downregulated the chemokine receptors CXCR4 and CXCR7. To reverse RAD001 resistance, PBRM1 knockdown was conducted in A498-RAD10 cells. PBRM1 knockdown partially restored sensitivity to RAD001 while inducing CXCR7 but not CXCR4 expression. In A498-RAD10 cells, the CXCR7 transcriptional repressor YY1 is overexpressed and bound to the CXCR7 promoter. As CXCR4 was robustly downregulated in A498-RAD10, and the PBRM1 knockdown only partially restored RAD001 sensitivity, CXCR4 was transfected into A498-RAD10 (A498-RAD10-CXCR4). CXCR4 completely restored RAD001 sensitivity in resistant cells while reducing PBRM1 expression, implying negative feedback. Interestingly, A498-RAD10 cells were cross-resistant to cabozantinib, the tyrosine kinase inhibitor used in first-line treatment of mRCC with nivolumab. Cabozantinib resistance of A498-RAD10 cells was reversed by PBRM1 knockdown or CXCR4 re-expression, mimicking the RAD001 resistance. A498-CABO4-resistant cells were developed and showed PBRM1 overexpression and downregulated CXCR4 and CXCR7. In silico data supported a context‑dependent role of PBRM1 in ccRCC patients. To the best of our knowledge, this is the first description of a mechanism of RAD001 and cabozantinib resistance through PBRM1 overexpression and CXCR7/CXCR4 downregulation and suggest new therapeutic perspective for cabozantinib-resistant patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13149507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A20 enhances the migration and metastasis of gastric cancer cells by promoting occludin degradation.","authors":"Yu-Ting Kuo, Hao-Chen Wang, Yan-Shen Shan","doi":"10.1038/s41420-026-03082-2","DOIUrl":"10.1038/s41420-026-03082-2","url":null,"abstract":"<p><p>Chronic inflammation is a well-established risk factor in the development of gastric cancer (GC). Tumor necrosis factor α-induced protein 3 (TNFAIP3, also known as A20) is an inflammation-associated protein that functions as an oncogene in various cancers, but the role of A20 in GC progression remains unclear. In this study, clinical analyses revealed that elevated A20 expression in GC patients was significantly associated with increased tumor aggressiveness and metastatic potential. Functionally, A20 overexpression enhanced GC cell migration, whereas its knockdown suppressed this effect. Moreover, A20 promoted epithelial-mesenchymal transition and reduced the tight junction protein occludin. Mechanistically, A20 induced occludin endocytosis and lysosomal degradation via its ovarian tumor (OTU) domain. Pull-down assays revealed that A20 interacts with the migration-related protein RhoA, increasing its stability and thereby sustaining ROCK2 phosphorylation, which contributes to occludin degradation. PLA further showed that mutation of the OTU domain disrupted the interaction between A20 and RhoA in AGS cells, indicating the necessity of the OTU domain for this interaction. In conclusion, our findings demonstrate that A20 promotes GC cell migration by stabilizing RhoA and facilitating occludin degradation, underscoring A20 as a potential therapeutic target to inhibit GC metastasis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13153315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TUFM: a central regulator in mitochondrial quality control and beyond.","authors":"Xuanyi Li, Liangjie Dong, Tian Xiao, Jiayi Chen, Hang Ye, Siyi Zhu, Fulin Chen, Yuan Yu","doi":"10.1038/s41420-026-03075-1","DOIUrl":"10.1038/s41420-026-03075-1","url":null,"abstract":"<p><p>Tu translation elongation factor, mitochondrial (TUFM) is a highly conserved, nuclear-encoded GTPase that is indispensable for mitochondrial protein synthesis. Beyond this canonical function, TUFM has emerged as a central regulator of mitochondrial quality control (MQC), orchestrating mitochondrial biogenesis, dynamics, and mitophagy through a location-dictates-function paradigm. Its subcellular localization and activity are precisely regulated by post-translational modifications, including phosphorylation, lactylation, ubiquitination, and acetylation, which collectively dictate its functional outputs in cellular homeostasis and stress responses. TUFM also serves as a critical interface in host-pathogen interactions, where viruses often hijack its pro-mitophagic function to evade mitochondrial antiviral signaling. Functioning as a cellular fate switch, the TUFM-MQC axis determines context-dependent pathological outcomes: its hyperactivation promotes cell growth and fuels oncogenesis, whereas its deficiency exacerbates cell death and contributes to neurodegeneration, inflammatory damage, and metabolic dysfunction. This review synthesizes current mechanistic insights into TUFM as a central MQC coordinator and delineates how its functional imbalance redirects cellular trajectories toward survival or death. Deciphering the regulatory logic and spatiotemporal dynamics of this pivotal hub offers promising avenues for developing targeted strategies to restore cellular homeostasis across a spectrum of diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13153400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant-divergent death: Omicron intensifies bystander T-cell apoptosis via GDF15-BCL2L13.","authors":"Chao Gao, Hanbing Chen, Ying Chi, Xinxing Lu, Jiahuang Li, Ying Tang, Ruixuan Yu, Nan Shi, Ling Liu, Jianfeng Xie, Haibo Qiu, Jie Chao, Shufeng Li","doi":"10.1038/s41420-026-03079-x","DOIUrl":"10.1038/s41420-026-03079-x","url":null,"abstract":"<p><strong>Background: </strong>Severe Omicron cases present profound lymphocytopenia, suggesting variant-specific immune injury.</p><p><strong>Results: </strong>We identify CD63 as a conserved T-cell host factor supporting ACE2-independent SARS-CoV-2 entry. Despite lower intracellular viral loads than the ancestral strain, Omicron elicits enhanced T-cell apoptosis largely through a bystander mechanism. Omicron-stimulated epithelial cells secrete GDF15, which upregulates the pro-apoptotic protein BCL2L13 in T cells and thereby remotely accelerates apoptosis in uninfected bystanders. Functionally, recombinant GDF15 increases BCL2L13 and apoptosis, while genetic dampening of BCL2L13 blunts Omicron-specific high-intensity bystander death. In clinical samples, plasma GDF15 associates with mortality, SOFA scores, and lower lymphocyte counts, bridging the epithelial-immune axis to patient outcomes.</p><p><strong>Conclusions: </strong>Our data delineate a two-track model of Omicron immune injury-CD63-enabled T-cell entry plus GDF15-BCL2L13-driven bystander apoptosis-that reconciles lower epithelial cytopathicity with deeper T-cell depletion in critical disease. These findings nominate the GDF15-BCL2L13 axis as a mechanistic marker and potential point of intervention.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models.","authors":"Chiara Parodi, Antonella Lettieri, Paolo Grazioli, Elisabetta Di Fede, Sara Grassi, Esi Taci, Andrea Toscani, Simona Prioni, Stefano Rebellato, Elisa Adele Colombo, Silvia Rasetti, Alessandro Cutarelli, Milena Mariani, Stefania Corti, Palma Finelli, Alessandro Prinetti, Grazia Fazio, Angelo Selicorni, Luciano Conti, Cristina Gervasini, Valentina Massa","doi":"10.1038/s41420-026-03085-z","DOIUrl":"10.1038/s41420-026-03085-z","url":null,"abstract":"<p><p>Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that affects almost any organ, including the central nervous system. It leads to a wide range of neurodevelopmental delays, and there are currently no available clinical treatments. CdLS is caused by pathogenic variants in one of the 7 genes coding for the cohesin complex, a multimeric structure responsible for sister chromatid cohesion, or for cohesin ring-interacting proteins. Additionally, altered regulation of molecular pathways during development, including the canonical WNT pathway, can cause CdLS malformations. In our study, we evaluated the positive effects of using lithium as an activator of the canonical WNT pathway to ameliorate neural CdLS phenotype. We have exploited accurate two-dimensional (2D) and three-dimensional (3D) human central nervous system in vitro models representing disease-related neurobiological phenotypes: induced pluripotent stem cells of human origin (hiPSCs) differentiated into neural precursors, neurons, and brain organoids (BOs). CdLS models demonstrate alterations in proliferation and differentiation capabilities when mimicking HDAC8 haploinsufficiency. Furthermore, RNA-seq analysis of BOs revealed that both neuronal differentiation and the WNT pathway are downregulated when treated with the HDAC8 inhibitor alone. Following lithium treatment, cells show an enhanced ability to differentiate into the neuronal lineage. Additionally, our working hypothesis is that a specific mechanism may exist that, by connecting lipid metabolism, canonical WNT pathway, and cell death, results in typical CdLS neurodevelopmental deficits.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AMPK is dispensable for physiological podocyte and glomerular functions but prevents glomerular fibrosis in experimental diabetes.","authors":"Swayam Prakash Srivastava, Olivia Kopasz-Gemmen, Abhiram Kunamneni, Aaron Thurman, Shota Yoshida, Eden Ozkan, Vinamra Swaroop, Rahul Nanwani, Ajan Arora, Arya Joshi, Om Khuperkar, Mariam Hamed, Mihir Suresh Bharadwaj, Niloy Islam, Adesh Urval, Junying Wang, Sungki Hong, Keizo Kanasaki, Daisuke Koya, Ken Inoki","doi":"10.1038/s41420-026-03078-y","DOIUrl":"10.1038/s41420-026-03078-y","url":null,"abstract":"<p><p>AMP-activated protein kinase (AMPK) has been postulated to be crucial in regulating various renal physiology and pathophysiology processes, including energy metabolism, ion and water transport, inflammation, and hypertrophy. However, the specific roles of AMPK in podocytes, cells critical for maintaining glomerular filtration, have not been fully explored using genetic model animals. In this study, we generated mice lacking both AMPK α1 and α2 catalytic subunits in glomerular podocytes (pmut). Our findings revealed that, surprisingly, AMPK is dispensable for normal podocyte function. These knockout mice could live as long as their wild-type littermates without showing any pathological alterations in their glomeruli or glomerular function at two years of age. However, under diabetic conditions, the diabetic pmut mice exhibited increased lipid and collagen accumulation and an elevated expression of mesenchymal proteins in their glomeruli. They also showed more significant albuminuria compared to control diabetic mice. Under high-glucose culture conditions, glomeruli isolated from pmut mice showed reduced expression of mitochondrial genes (e.g., Ndufv2) and increased leakage of mitochondrial components. Additionally, there was increased expression of genes associated with nucleotide-sensing and pro-inflammatory pathways (including mb21d2, IL-1β, and NF-κB). These observations suggest that while AMPK is not necessary for podocyte function in healthy kidneys, it is crucial for preventing glomerular fibrosis resulting from lipotoxicity and inflammation under diabetic conditions.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13153347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabinoid type 2 receptor regulates skeletal muscle regeneration by NLRP3-GSDMD mediated macrophage pyroptosis after injury.","authors":"Xinjie Li, Haomiao Yuan, Shuyang Mu, Jiaqing Pan, Fuyuan Zhang, Shukui Du, Jin Liu, Anran Qu, Yingfu Sun, Linlin Wang, Ping Huang, Rui Zhao, Dawei Guan","doi":"10.1038/s41420-026-03077-z","DOIUrl":"10.1038/s41420-026-03077-z","url":null,"abstract":"<p><p>Skeletal muscle repair after injury requires coordinated immune responses. The cannabinoid type 2 receptor (CB2R) has been implicated in this process; however, its molecular mechanism in regulating inflammation and muscle regeneration, particularly whether it involves modulating macrophage pyroptosis-a specific pro-inflammatory cell death-remains elusive. This study proposes and validates a novel mechanism: CB2R activation protects skeletal muscle by inhibiting the PI3K/AKT/NF-κB signaling axis, thereby suppressing NLRP3 inflammasome-mediated pyroptosis in macrophages and ultimately fostering a pro-regenerative microenvironment. Using a mouse contusion model and conditioned medium assays, we demonstrate that CB2R deficiency exacerbates macrophage pyroptosis, elevates inflammatory mediators, and impairs muscle repair. This effect is driven by hyperactivation of the PI3K/AKT/NF-κB pathway, as blocking this pathway alleviated the inflammatory response and restored the expression of muscle regeneration markers. Furthermore, inflammatory signals released from CB2R-deficient macrophages directly impaired the development of muscle cells in the conditioned medium-based assay. Our findings uncover a novel non-cell-autonomous mechanism whereby CB2R supports skeletal muscle regeneration by restraining macrophage-driven inflammation and maintaining a repair-permissive environment, providing new insights into skeletal muscle repair from the perspective of the regenerative microenvironment and further expand the current understanding of muscle regeneration following injury. This work provides a robust mechanistic rationale for repurposing CB2R agonists as promising therapeutic strategies for muscle injury.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate-mediated NK cell dysfunction as a prognostic marker and therapeutic target in breast cancer.","authors":"Simone Ielpo, Francesca Barberini, Alice Gaiba, Camilla Baronti, Marco Greppi, Valentina Obino, Silvia Ravera, Nicole Bussola, Adele De Ninno, Luca Businaro, Valentina Mussi, Silvia Pomella, Emanuele Agolini, Monica Benvenuto, Chiara Focaccetti, Emanuela Marcenaro, Roberto Bei, Giovanni Barillari, Silvia Pesce, Loredana Cifaldi, Ombretta Melaiu","doi":"10.1038/s41420-026-03063-5","DOIUrl":"10.1038/s41420-026-03063-5","url":null,"abstract":"<p><p>Lactate is recognized as a crucial signalling molecule within the tumor microenvironment, where it shapes immune responses by modulating various cell populations, including T cells and macrophages. However, its effect on natural killer (NK) cells, key effectors of early antitumor immunity, remains poorly understood. This study investigates how intratumoral lactate accumulation affects NK cell function in breast cancer, a neoplasm characterized by elevated glycolytic flux. An in-silico analysis of 882 breast cancer patients revealed that high lactate metabolism is inversely correlated with NK cell activation genes and is associated with poor prognosis. To corroborate these findings, NK cells from healthy donors were cultured under lactate-rich or control conditions. Lactate exposure impaired NK cell proliferation, downregulated activation markers and cytotoxic molecules, disrupted mitochondrial bioenergetics, and induced lipid accumulation, as demonstrated by flow cytometry, metabolic profiling, and Raman spectroscopy. Functional assays using microfluidic devices and degranulation tests revealed that lactate-exposed NK cells exhibited reduced chemotaxis and diminished cytotoxicity against MCF-7 and MDA-MB-231 breast cancer spheroids, accompanied by decreased CXCL9 and CXCL10 production. Pharmacologic inhibition of lactate transport, via Syrosingopine or MSC-4381 and AZD3965 combination, restored NK cell cytotoxicity in tumor co-cultures, as shown by increased NK cell degranulation, caspase-3/7-mediated tumor apoptosis, and spheroid shrinkage. Finally, GPR81 deletion mirrored these effects, enhancing NK cell activity. These findings identify lactate as a driver of NK cell suppression and highlight lactate transport and receptor targeting as a strategy to enhance NK cell-based immunotherapies in breast cancer and other lactate-rich tumors.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13149829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}