Androgen receptor activity tunes effector and memory CD8 T cell responses

Androgen hormones regulate the activity of myriad cells of the immune system and are strong drivers of sex differences in disease susceptibility, yet little is known of the mechanisms by which androgen hormones influence immunity. This study identifies androgen receptor (AR) as a key regulator of CD8 T cell differentiation and function, showing that AR acts as an epigenetic repressor in CD8 T cells, restrains effector expansion during infection, and limits memory protection, thereby providing a mechanistic basis for sex differences in immunity. Using mouse models of infection and single-cell profiling of prostate tumors from patients treated with androgen axis inhibition plus anti-PD-1 therapy, this study demonstrates that AR inhibition enhances effector T cell responses both during infection and in the anti-tumor response. These results position AR as a transcriptional brake on CD8 T cell function, linking sex-biased immunity to therapeutic opportunities in infection, cancer, and immunotherapy.