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It highlights mechanisms including loss of chromosome Y (LOY) remodeling toward immunosuppression, X-inactivation escape that supports antitumor immunity, and endocrine signaling shaping T-cell exhaustion and PD-L1/PD-1 and CD8+ T-cell activity for precision immuno-oncology 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sex?",{"text":72,"@type":64},"Androgen receptor signaling is linked to T-cell exhaustion via PD-1 transcriptional activation in males, while estrogen and estrogen-receptor pathways modulate cancer progression through PD-L1 expression and CD8+ T-cell activation in females.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},370931,1790315727,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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\nChina Medical University, China  \nREVIEWED BY  \nShaohua Qi,  \nHouston Methodist Research Institute, United States  \nJie Xian,  \nUniversity of California, San Diego, United States  \nPablo Damian-Matsumura,  \nUniversidad Auto´noma Metropolitana, Mexico  \n*CORRESPONDENCE  \nMing-Yu Wang  \n[wangmy@lzu.edu.cn](wangmy@lzu.edu.cn)[ ](wangmy@lzu.edu.cn)Cai-Juan Bai  \n [Baicj1985@hotmail.com](Baicj1985@hotmail.com)  \nRECEIVED 07 June 2025  \nACCEPTED 30 August 2025  \nPUBLISHED 12 September 2025  \nCITATION  \nZhang C-M, Ge Z-B, Zhou H-H, Wei M-X, Ding X-Y, Lin Z-Z, Wang M-Y and Bai C-J (2025) Sex chromosomes/hormones and the tumor microenvironment of nonreproductive cancers.  \nFront. Immunol. 16:1642956 .  \ndoi: 10.3389/fimmu.2025.1642956  \nCOPYRIGHT  \n© 2025 Zhang, Ge, Zhou, Wei, Ding, Lin, Wang and Bai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nSex chromosomes/hormones and the tumor microenvironment of nonreproductive cancers  \nChun-Miao Zhang1, Zhong-Bo Ge2, Hai-Hong Zhou 3,4, Meng-Xiao Wei 2, Xin-Yuan Ding 2, Zhe-Zheng Lin 2, Ming-Yu Wang 2* and Cai-Juan Bai 5,6*  \n1 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China, 2 Ministry Of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China, 3Centre for Translational Medicine, Gansu Provincial Academic Institute for Medical Research, Lanzhou, China, 4Centre for Translational Medicine, Sun Yat-Sen University Cancer Center Gansu Hospital, Lanzhou, China, 5 National Health Commission Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China, 6The Institute of Clinical Research and Translational Medicine, Gansu Provincial Hospital, Lanzhou, China  \nCancer exhibits profound sexual dimorphism in incidence and therapeutic outcomes, driven by the interplay between biological sex determinants and immune regulation. Besides established environmental risk factors (e.g., malepredominant smoking/alcohol consumption), emerging evidence identifies the tumor immune microenvironment (TIME) as a pivotal mediator of sex disparities in carcinogenesis and immunotherapy response. This review synthesizes recent advances in two fundamental mechanisms: (1) Sex chromosome biology: Recent studies delineate the Ubiquitous loss of chromosome Y (LOY) of male cancers that promotes immunosuppressive TIME remodeling, while X-chromosome inactivation escape in females enhances antitumor immunity; (2) Endocrine regulation: Androgen receptor signaling induces T-cell exhaustion via PD-1 transcriptional activation in males. Estrogen-ERa boosts cancer progression via PD-L1 high expression, whereas ERb inhibits cancer progression via CD8+ T cell activation in females. This mechanistic synthesis provides actionable strategies for precision immuno-oncology trials targeting sex-based immunological divergence.  \nKEYWORDS  \nsexual dimorphism, tumor microenvironment, loss of Y chromosome, X-chromosome inactivation escape, sex hormone, antitumor immunity, non-reproductive cancer  \nFrontiers in Immunology 01 [frontiersin.org](frontiersin.org)  \n1 Introduction  \nCancer remains a leading cause of global mortality (1) . Population-based studies reveal significant sex-based disparities in the incidence of most non-reproductive cancers (2) . This dichotomy extends to morta","cbCaisSzIIqXKaG4","https://ap.wps.com/l/cbCaisSzIIqXKaG4","pdf",1996590,"English","# Introduction\n## Sex-based disparities in non-reproductive cancers\n## Lifestyle, chromosomal determinants, and hormonal regulation\n# Sex chromosomes as drivers of cancer disparities\n## X-inactivation escape in females\n## X-monosomy vulnerability in males","[{\"question\":\"How does the tumor immune microenvironment (TIME) relate to sex disparities in cancer?\",\"answer\":\"TIME is presented as a pivotal mediator linking biological sex determinants to differences in carcinogenesis and immunotherapy response.\"},{\"question\":\"What role does loss of chromosome Y (LOY) play in male cancers?\",\"answer\":\"LOY in male cancers is described as promoting immunosuppressive TIME remodeling, contributing to sex-linked differences in outcomes.\"},{\"question\":\"How do androgen and estrogen pathways affect antitumor immunity differently by sex?\",\"answer\":\"Androgen receptor signaling is linked to T-cell exhaustion via PD-1 transcriptional activation in males, while estrogen and estrogen-receptor pathways modulate cancer progression through PD-L1 expression and CD8+ T-cell activation in females.\"}]","Sex chromosomes/hormones and the tumor microenvironment of nonreproductive cancers | PDF",1790190858,25]