Zhang Chun-Miao, Ge Zhong-Bo, Zhou Hai-Hong, Wei Meng-Xiao, Ding Xin-Yuan, Lin Zhe-Zheng, Wang Ming-Yu, Bai Cai-Juan
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.
Ministry Of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China.
Front Immunol. 2025 Sep 12;16:1642956. doi: 10.3389/fimmu.2025.1642956. eCollection 2025.
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.
