Nature cancer最新文献

{"title":"A micropeptide encoded by the lncRNA USP30-AS1 promotes tumor growth by attenuating cGAS–STING–type I IFN signaling in macrophages","authors":"Xingwen Wang, Yi Zhang, Jiangwen Ma, Qingyu Lin, Zhenghang Wang, Guixue Hou, Yutong Wei, Minqiao Lu, Meiqi Wang, Tianyu Li, Shanliang Zheng, Wenxin Zhang, Yafan Gong, Tianqi Guan, Hao Liu, Xiaotian Zhang, Li Li, Ying Hu","doi":"10.1038/s43018-026-01195-2","DOIUrl":"10.1038/s43018-026-01195-2","url":null,"abstract":"Immune checkpoint blockade has achieved remarkable success in cancer treatment; however, enhancing its efficacy remains a challenge. Here we identified an immunoregulatory micropeptide encoded by the long noncoding RNA USP30-AS1 gene, highly expressed in tumor-associated macrophages. The so-designated UEIS (USP30-AS1-encoded immune suppressor) drives macrophages toward a protumorigenic phenotype, thereby inhibiting antitumor T cell immunity. Mechanistically, UEIS is induced in macrophages by cGAS–STING–type I interferon signaling at a relatively late stage following tumoral DNA stimulation, and exerts a negative feedback regulation on the type I interferon signaling by forming biomolecular condensates with TBK1, thereby inhibiting its interaction with STING. Both an intrinsically disordered region and an alpha helix at the extreme N terminus of UEIS were essential for its function. A peptide designed to disrupt UEIS–TBK1 condensation successfully inhibited UEIS function in tumor-associated macrophages, leading to reduced tumor growth and increased response to immune checkpoint blockade. Thus, these findings highlight UEIS as a promising therapeutic target for cancer treatment. Hu and colleagues report that a micropeptide encoded by the lncRNA USP30-AS1 promotes tumor growth by undergoing phase separation with TBK1 and attenuating cGAS–STING–type I IFN signaling in tumor-associated macrophages.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 7","pages":"1047-1063"},"PeriodicalIF":28.0,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPNMB-directed CAR-T cell therapies for solid tumors","authors":"Christopher W. Mount, Marcela V. Maus","doi":"10.1038/s43018-026-01201-7","DOIUrl":"10.1038/s43018-026-01201-7","url":null,"abstract":"Target discovery remains a considerable challenge in the development and translation of chimeric antigen receptor (CAR)-T cell therapies for solid tumors. Two reports in Nature and Nature Cancer now detail promising preclinical and translational efforts to target GPNMB in alveolar soft part sarcoma and glioblastoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 8","pages":"1171-1173"},"PeriodicalIF":28.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IDH1-mutant vaccine in newly diagnosed astrocytoma: final analysis of the multicenter, single-arm, open-label, first-in-human phase 1 NOA16 trial","authors":"Lukas Bunse, Katharina Lindner, Antje Wick, Angelika Freitag, Lisa-Marie Lanz, Dominic Edelmann, Abigail Suwala, Michael O. Breckwoldt, Inga Harting, Felix Sahm, Richard F. Schlenk, Anita Schmitt, Oliver Schnell, Jörg Hense, Martin Misch, Dietmar Krex, Monika Denk, Juliane Walz, Joachim P. Steinbach, Andreas von Deimling, Michael Schmitt, Theresa Bunse, Ghazaleh Tabatabai, Martin Bendszus, Isabel Poschke, Wolfgang Wick, Michael Platten","doi":"10.1038/s43018-026-01199-y","DOIUrl":"10.1038/s43018-026-01199-y","url":null,"abstract":"The clonal glioma driver mutation IDH1R132H gives rise to a major histocompatibility class II-restricted neoepitope. A multicenter, first-in-human phase 1 trial met its prespecified primary endpoints by demonstrating safety and immunogenicity of an IDH1-R132H peptide vaccine (IDH1-vac) integrated into standard of care in 33 participants with newly diagnosed grade III and IV (World Health Organization classification 2007) IDH1-R132H+ astrocytomas (NOA16). Here we report on the clinical and immunological long-term follow-up of this trial as secondary and translational endpoints. The 8-year progression-free and overall survival (OS) rates were 0.42 (confidence interval (CI): 0.24–0.59) and 0.66 (CI: 0.46–0.79), respectively. For participants with grade IV astrocytoma, median OS was 106.1 months (CI: 39.6–not estimable (NE)), comparing favorably to the published median OS in this population ranging from 31.6–56.4 months. Within the responder group, sustained antibody responses to IDH1-R132H were associated with a favorable long-term clinical course. IDH1-vac-induced T cell responses were detected in the inflamed brain lesion of an IDH1-vac-associated pseudoprogression, whereas no IDH1-vac-induced T cells were found in participants with early progressive disease. The favorable long-term outcome of the NOA16 cohort supports investigating IDH1-vac in persons with newly diagnosed grade 3 and 4 (World Health Organization classification 2021) IDH-mutant astrocytomas in a randomized phase 2 trial (ClinicalTrials.gov identifier: NCT02454634 ). In the multicenter, single-arm, open-label, first-in-human phase 1 NOA16 trial, Platten and colleagues report the long-term clinical and immunological follow-up outcomes of a vaccine targeting mutant IDH1 in persons with astrocytoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 8","pages":"1300-1311"},"PeriodicalIF":28.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-026-01199-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors","authors":"Franz J. Zemp, Zackariah Breckenridge, Hyojin Song, Gurveer S. Gill, Taye L. Louie, Kiran Narta, Hongrui Liu, Yeon Suh, Louisa Guignard, Edna Ayerim Mandujano-Tinoco, Nicolás Collao, Joanna Pyczek, Kristofor K. Ellestad, Jada Curry, Jethro Langley, Cini John, Laura K. Mah, Jahanara Rajwani, Danyel Evseev, Madison Turk, Sacha Benaoudia, Jonathan Alex, Victor Naumenko, Varsha Thoppey Manoharan, Mobina Kazemi Mehrabadi, Harmony A. Smith, Geneece N. Y. Gilbert, Aaron Gillmor, Ted B. Verhey, Hayley M. Todesco, Katalin Osz, Bo-Young Ahn, Ana Bogossian, Colleen Anderson, Saif Sikdar, Shahrbano Rukunuddin, Tarek A. Bismar, Daniel Y. C. Heng, Keith Lawson, W. Marston Linehan, Haley Pedersen, Paul M. K. Gordon, John B. McIntyre, John MacGregor, Livia Garzia, Kathy Brodeur-Robb, Lisa DiFrancesco, Travis Ogilvie, Patrick Schöffski, Agnieszka Wozniak, Robert A. Holt, John Bell, Donna L. Senger, Victor Lewis, Michael Monument, Omar Khan, Lou Baudrier, Pierre Billon, Vincent Gabriel, Jeff Biernaskie, Kyle Potts, Kiril Trpkov, Kevin Hay, Jennifer Quizi, Jennifer Chan, Ramy Saleh, Jan Willem Henning, Nicole L. Prokopishyn, Mona Shafey, A. Sorana Morrissy, Douglas J. Mahoney","doi":"10.1038/s43018-026-01194-3","DOIUrl":"10.1038/s43018-026-01194-3","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)—an MiT/TFE-family fusion-driven protein—as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies. Zemp et al. found glycoprotein NMB (GPNMB) as a targetable antigen for MiT/TFE-family fusion-driven soft-part sarcoma and translocation renal cell carcinoma and developed and tested a GPNMB-directed chimeric antigen receptor T cell product in preclinical models and in first-in-human setting.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 8","pages":"1189-1207"},"PeriodicalIF":28.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term outcomes of adjuvant metronomic capecitabine in locoregionally advanced nasopharyngeal carcinoma: a randomized, controlled, multicenter, phase 3 study","authors":"Ya-Lan Tao \u0000 (, ), Dong-Hong Wu \u0000 (, ), Qin Zhou \u0000 (, ), Kun-Yu Yang \u0000 (, ), Feng Jin \u0000 (, ), Xiao-Dong Zhu \u0000 (, ), Mei Shi \u0000 (, ), Guo-Qing Hu \u0000 (, ), Yan Sun \u0000 (, ), Hong-Fen Wu \u0000 (, ), Hui Wu \u0000 (, ), Qin Lin \u0000 (, ), Hui Wang \u0000 (, ), Ye Tian \u0000 (, ), Ning Zhang \u0000 (, ), Xi-Cheng Wang \u0000 (, ), Liang-Fang Shen \u0000 (, ), Zheng-Zheng Liu \u0000 (, ), Jing Huang \u0000 (, ), Xiu-Ling Luo \u0000 (, ), Ling Li \u0000 (, ), Jian Zang \u0000 (, ), Qi Mei \u0000 (, ), Bao-Min Zheng \u0000 (, ), Dan Yue \u0000 (, ), Jing Xu \u0000 (, ), San-Gang Wu \u0000 (, ), Lei Chen \u0000 (, ), Wen-Fei Li \u0000 (, ), Guan-Qun Zhou \u0000 (, ), Rui Sun \u0000 (, ), Rui Guo \u0000 (, ), Yuan Zhang \u0000 (, ), Cheng Xu \u0000 (, ), Jia-Wei Lv \u0000 (, ), Ying Guo \u0000 (, ), Hui-Xia Feng \u0000 (, ), Ling-Long Tang \u0000 (, ), Fang-Yun Xie \u0000 (, ), Xu Liu \u0000 (, ), Ying Sun \u0000 (, ), Jun Ma \u0000 (, ), Yan-Ping Mao \u0000 (, ), Yu-Pei Chen \u0000 (, )","doi":"10.1038/s43018-026-01193-4","DOIUrl":"10.1038/s43018-026-01193-4","url":null,"abstract":"Here we report long-term outcomes of adjuvant metronomic capecitabine in patients with locoregionally advanced nasopharyngeal carcinoma. In this multicenter, open-label, parallel-group, randomized, controlled, phase 3 trial, 406 patients who had completed definitive chemoradiotherapy were randomly assigned (1:1) to receive either adjuvant metronomic capecitabine (650 mg m−2 twice daily for 1 year) or observation. The primary endpoint was failure-free survival; secondary endpoints included overall survival (OS), distant failure-free survival, locoregional failure-free survival, and safety, as reported in this analysis. The trial met its primary endpoint. With a median follow-up of 71.3 months, metronomic capecitabine significantly improved OS (hazard ratio = 0.53, 95% confidence interval, 0.31–0.91, P = 0.019). Grade 3 adverse events occurred in 35 (17%) of 201 patients in the metronomic capecitabine group and 11 (6%) of 200 in the observation group; one (<1%) grade 4 neutropenia was reported. In a post hoc analysis, completion of the 1 year course was associated with improved OS, whereas dose reductions and relative dose intensity showed no association with OS. Patients with a higher post-radiotherapy neutrophil-to-lymphocyte ratio derived greater benefit from metronomic capecitabine. These findings support the long-term therapeutic benefit of adjuvant metronomic capecitabine in locoregionally advanced nasopharyngeal carcinoma. ClinicalTrials.gov identifier: NCT02958111 . In this randomized, controlled, multicenter phase 3 clinical trial, Ma and colleagues reported the long-term outcomes and the impact of drug exposure metrics of adjuvant capecitabine in patients with locoregionally advanced nasopharyngeal carcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 7","pages":"1149-1157"},"PeriodicalIF":28.0,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148361530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of ADSS2-mediated de novo AMP biosynthesis re-sensitizes acute myeloid leukemia to BH3 mimetics","authors":"Xin He, Lei Zhang, Yang Li, Song-Bai Liu, Zheng Li, Haojie Dong, Genevieve E. Baker, Le Xuan Truong Nguyen, Wei Chen, Jinhui Wang, Zhilian Jia, Xiyuan Lu, Yi-Chun Lin, Zunsong Hu, Umesh Prasad Yadav, Meng Liu, Lianjun Zhang, Zhenhua Chen, Xiwei Wu, Jianjun Chen, Chun-Wei Chen, Stefano Tiziani, Weidong Hu, Ya-Huei Kuo, Sheng-Li Xue, Yong Zhang, Min Li, Yaoqiu Zhu, Guido Marcucci, Zhaohui Gu, J. Jefferson P. Perry, Yun Lyna Luo, Ling Li","doi":"10.1038/s43018-026-01184-5","DOIUrl":"10.1038/s43018-026-01184-5","url":null,"abstract":"De novo purine synthesis is required to maintain tumor growth; however, its impact on therapy resistance remains unclear. Here, through a dynamic BH3-priming-based CRISPR screen, we found that deletion of ADSS2, which encodes the adenylosuccinate synthase 2 enzyme essential for adenosine monophosphate (AMP) synthesis, re-sensitizes drug-resistant acute myeloid leukemia cells to venetoclax and a myeloid cell leukemia-1 (MCL1) inhibitor. Single-cell sequencing analysis of patient-derived xenograft samples revealed a positive association of high ADSS2 activity in TP53-mutant cells with poor responsiveness to venetoclax. We developed an ADSS2 antagonist, which synergized with BH3 mimetics to promote apoptosis in preclinical models. Mechanistically, sensitization mediated by ADSS2 targeting correlated with downregulated AMP-activated protein kinase activity, which in resistant cells promotes mitophagy to eliminate damaged mitochondria after BH3 mimetic treatment. These data show that AMP synthesis promotes BH3 mimetic resistance and that combining ADSS2 targeting with BH3 mimetics represents a promising anti-cancer approach. He et al. demonstrate that ADSS2 deletion re-sensitizes AML to venetoclax by impairing mitophagy in response to the drug and develop an ADSS2 inhibitor that synergizes with BH3 mimetics in resistant AML.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 6","pages":"944-963"},"PeriodicalIF":28.0,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148314819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA shapes GBM immune responses in a sex-dependent manner","authors":"Malcolm F. McDonald, Benjamin Deneen","doi":"10.1038/s43018-026-01183-6","DOIUrl":"10.1038/s43018-026-01183-6","url":null,"abstract":"Glioblastoma is a deadly primary brain tumor with a complex immunosuppressive microenvironment that poses a therapeutic challenge. A study now demonstrates that GABAB signaling enhances immunosuppressive programs of myeloid-derived suppressor cells in female models of preclinical glioblastoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 7","pages":"1025-1026"},"PeriodicalIF":28.0,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GABA signaling activation drives glioblastoma progression in female mice through myeloid-derived suppressor cells","authors":"Asmita Pathak, Palavalasa Sravya, Bruno Colon, Erika Ciervo, Yadi Zhou, Oriana Y. Teran Pumar, Brandon Emanuel León, Jonathan Mitchell, Pedro Henrique Assenza Tavares Coroa, Beatriz Mateo-Victoriano, Andrew J. Scott, Durga Prasad Gannamedi, Harrison K. A. Wong, Li Zhang, Juyeun Lee, Kristen Kay, Efe Karaca, Diana H. Chin, Haleh Amirian, Irem Karaman, Preyasha Shrestha, Katelyn Sellick, Danielle Dean, Daniel Bilbao Cortes, Jashodeep Datta, Scott M. Welford, Maria Clara Franco, Kiran Kurmi, Ashish H. Shah, Feixiong Cheng, Justin D. Lathia, Priyamvada Rai, David B. Lombard, Costas A. Lyssiotis, Dionysios C. Watson, Michele Ceccarelli, Daniel R. Wahl, Defne Bayik","doi":"10.1038/s43018-026-01192-5","DOIUrl":"10.1038/s43018-026-01192-5","url":null,"abstract":"Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying distinct immune-cancer interactions are poorly understood. Here we identify γ-aminobutyric acid (GABA) as a female-specific driver of GBM-promoting immune response. We demonstrated that GABA receptor B (GABBR) signaling enhances the T cell suppressive function of granulocytic myeloid-derived suppressor cells (gMDSCs) from female mice by upregulating the cationic amino acid transporter 2–L-arginine–nitric oxide synthase 2 (NOS2) pathway. GABBR agonism promotes GBM growth in female preclinical models through gMDSCs, while GABBR antagonism extends survival and reduces NOS2 in tumor-infiltrating gMDSCs only in female mice. Immune cells from female participants with GBM have enriched GABA transcriptional signatures and a higher GABA concentration compared to male counterparts. Collectively, these results highlight the sex-specific immunomodulatory role of GABA in tumorigenesis, supporting future assessment of GABA pathway inhibitors for cancer immunotherapy. Pathak et al. unveil a female vulnerability for glioblastoma according to a mechanism that relies on γ-aminobutyric acid receptor-mediated signaling on granulocytic myeloid-derived suppressor cells, which in turn triggers T cell suppression, thereby promoting tumor progression in preclinical models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 7","pages":"1080-1093"},"PeriodicalIF":28.0,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-026-01192-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The future of tertiary lymphoid structures in cancer immunotherapy as biomarkers and therapeutic targets","authors":"Hye Mi Kim, Tejashree Joglekar, Tina Cascone, Tullia C. Bruno","doi":"10.1038/s43018-026-01188-1","DOIUrl":"10.1038/s43018-026-01188-1","url":null,"abstract":"Immuno-oncology therapy has provided a paradigm shift in cancer treatment, and immune checkpoint inhibitors are now standard of care for several solid tumors. However, durable clinical responses with immune checkpoint inhibitors are often restricted to only 20% of patients. The formation of tertiary lymphoid structures within patient tumors is recognized as a favorable prognostic biomarker for treatment response. Thus, therapeutic induction and targeting of these structures can offer a potential approach for converting immune-excluded tumors into immune-infiltrated tumors, which could contribute to augmented and more-durable anti-tumor responses. Bruno and colleagues provide an overview of tertiary lymphoid structures as biomarkers and potential therapeutic targets in the cancer immunotherapy era.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 7","pages":"1021-1024"},"PeriodicalIF":28.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PID1 generates oxysterols to switch macrophage cell fates for improved antitumor immunity","authors":"Yuxiao Zheng, Qi Wang, Chen Dong, Qiong Wang, Mingshun Han, Haiqing Zhao, Shuang Wang, Longlong Chen, Xiaoli Zhang, Dan Yang, Jun Xiao, Zhihuan Chew, Zhenfei Xie, Lei Yang, Jinyong Fan, Xin Zheng, Dezhen Tu, Weiyun Li, Lingming Zheng, Lijian Hui, Xiaowu Huang, Jinsong Li, Huiru Tang, Bin Wei, Hongyan Wang","doi":"10.1038/s43018-026-01189-0","DOIUrl":"10.1038/s43018-026-01189-0","url":null,"abstract":"Disordered cholesterol–oxysterol profiles are observed in the tumor microenvironment, yet their roles in tumor-associated macrophages (TAMs) remain underexplored. This study reveals that TAMs across human pan-cancers exhibit elevated phosphotyrosine interaction domain-containing protein 1 (PID1) expression and prominent immunosuppressive gene signatures. PID1 deficiency in myeloid cells upregulates low-density lipoprotein (LDL) receptor expression, thereby promoting LDL uptake and intracellular accumulation of free cholesterol and reactive oxygen species (ROS). Increased ROS drives cholesterol oxidation to generate the oxysterols 5α,6α-epoxycholesterol (5α,6α-EC) and 7β-hydroxycholesterol (7β-OHC), which inhibit mTOR–STAT6 signaling in macrophages. Pid1 deletion switches immunosuppressive macrophages toward an antitumor subtype that downregulates arginase 1 expression while upregulating proinflammatory cytokines, thereby potentiating CD8+ T cell-mediated immunosurveillance across multiple tumor types. Moreover, combination treatment with the oxysterol and chemotherapeutic agent 5-fluorouracil produces synergistically enhanced antitumor effects. Previous studies showed that cholesterol-derived oxysterols differentially regulate macrophage cell fates, with 25-OHC promoting the protumor and immunosuppressive phenotype of TAMs. Targeting PID1 reroutes cholesterol and ROS metabolism toward the production of 5α,6α-EC and 7β-OHC in TAMs, representing a promising immunometabolic strategy to restore antitumor immunosurveillance. Wang and colleagues show that phosphotyrosine interaction domain-containing protein 1, a protein involved in lipid metabolism, is upregulated in tumor-associated macrophages (TAMs) and its disruption reprograms TAMs in a phenotype promoting antitumor immunity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 9","pages":"1436-1453"},"PeriodicalIF":28.0,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}