Sex chromosomes/hormones and the tumor microenvironment of non-reproductive cancers
Chun-Miao Zhang1, Zhong-Bo Ge2, Hai-Hong Zhou3,4
1Key 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.
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.
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