Sex-based immune differences influence tumor progression in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) presents with higher incidence and poorer prognosis in males compared to females, yet the mechanisms underlying this sex disparity remains unclear. We investigated whether sex-specific immune responses contribute to differential tumor control using syngeneic and oral carcinogen-induced HNSCC mouse models., Female mice exhibited significantly reduced tumor burden, delayed progression and decreased metastatic potential compared to males. Immune profiling revealed a more robust antitumor immune landscape in females, characterized by heightened effector T cell activation, increased production of pro-inflammatory cytokines (IFN-γ, TNF-α), reduced expression of T cell exhaustion markers (PD-1, TIGIT), and a lower frequency of immunosuppressive myeloid-derived suppressor cells. Importantly, CD8⁺ T cell depletion in females abrogated the resistance to HNSCC in females, establishing CD8⁺ T cells as key mediators of sex-dependent antitumor immunity. Collectively, these findings demonstrate that enhanced effector T cell function coupled with reduced immunosuppression underlies improved tumor control in females and underscores the importance of integrating sex as a biological variable in immuno-oncology.