MINI REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1642956
This article is part of the Research TopicCommunity Series in Interaction of Cell Subtypes in Tumor Microenvironment, and Implications for Immunotherapy Volume IIView all 4 articles
Sex chromosomes/hormones and the tumor microenvironment of nonreproductive cancers
Provisionally accepted
Chun-Miao Zhang1Zhong-Bo Ge1
Haihong Zhou2Meng-Xiao Wei1Xin-Yuan Ding1Zhe-Zheng Lin1
Ming-Yu Wang1*
Cai-Juan Bai3*- 1Lanzhou University, Lanzhou, China
- 2Gansu Provincial Academic Institute for Medical Research, Lanzhou, China
- 3Gansu Provincial Hospital, Lanzhou, China
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Cancer 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., male-predominant 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-ERα boosts cancer progression via PD-L1 high expression, whereas ERβ 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.
Keywords: sexual dimorphism, Tumor Microenvironment, Loss of Y chromosome, X-chromosome inactivation escape, sex hormone, antitumor immunity, non-reproductive cancer
Received: 07 Jun 2025; Accepted: 30 Aug 2025.
Copyright: © 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) or licensor 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.
* Correspondence:
Ming-Yu Wang, Lanzhou University, Lanzhou, China
Cai-Juan Bai, Gansu Provincial Hospital, Lanzhou, China
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