AUTHOR=Zhang Chun-Miao , Ge Zhong-Bo , Zhou Hai-Hong , Wei Meng-Xiao , Ding Xin-Yuan , Lin Zhe-Zheng , Wang Ming-Yu , Bai Cai-Juan 

TITLE=Sex chromosomes/hormones and the tumor microenvironment of non-reproductive cancers

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1642956

DOI=10.3389/fimmu.2025.1642956

ISSN=1664-3224

ABSTRACT=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.