CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory.

Pharmacological inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, while their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunological T cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous anti-tumor T cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor (CAR)-T cells, and induced an RB-dependent T cell phenotype supportive of favorable responses to immune checkpoint blockade in melanoma patients. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost anti-tumor T cell immunity.