Androgen-mediated T cell suppression drives sex bias in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) exhibits a strong sex bias. However, the mechanisms underlying this disparity remain unclear. Using the Four Core Genotypes (FCG) mouse model to uncouple gonadal sex from sex chromosome complement influences, we investigated the contributions of sex hormones and sex chromosomes on HNSCC development and anti-tumor immunity. Male-biased tumor growth was confirmed in 4-NQO-induced oral lesions and orthotopic MOC1 tumors in both WT and FCG mice. Gonadal sex, rather than sex chromosomes, was identified as a primary driver of male tumor growth. While the interactive effects gonadal sex and possession of an XX-chromosome complement interacted to limit MOC1 tumor growth in FCG females. Mechanistically, in vitro dihydrotestosterone (DHT) exposure did not increase MOC1 proliferation and induced only modest transcriptomic changes, suggesting that tumor-extrinsic AR signaling promotes male tumor growth in vivo. Notably, sex differences in MOC1 tumor growth were eliminated in TCR⍺KO mice, implicating sex-specific T cell regulation in HNSCC sex biases. Interestingly, castration reduced MOC1 tumor burden and enhanced both T cell activation and infiltration into male MOC1 tumors, while greater CD8+ T cell responses in XX-possessing FCG females was suggestive of the interactive influence of sex chromosomes and sex hormones on female anti-tumor immunity. Together, these results identify sex-specific T cell regulation as a critical factor in HNSCC risk and highlight androgens as a potential therapeutic target to enhance tumor-specific immunity and immunotherapeutic efficacy in HNSCC patients.