Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity

Abstract

The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8⁺ T cells exhibited impaired effector and stem cell-like properties compared with female CD8⁺ T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8⁺ T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8⁺ T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8⁺ T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8⁺ T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.

Keywords: androgen receptor; sex differences in cancer; stem cell-like CD8(+) T cells; tumor immunity.