Abemaciclib differentially reshapes the immunopeptidome of breast cancer subtypes

The cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) Abemaciclib has demonstrated transformative potential in the treatment of hormone receptor-positive (HR+) breast cancer. Beyond its established role in cell cycle arrest, we reveal its capacity to enhance tumor immunogenicity by remodeling the immunopeptidome. Using a proteogenomic approach, we analyzed the antigenic repertoire of HR+ and triple-negative breast cancer (TNBC) models following Abemaciclib treatment. Our findings highlight a substantial increase in MHC-I presentation and antigen diversity, particularly in HR+ cells. This effect is mediated through Rb-dependent transcriptional and epigenetic reprogramming involving bromodomain and extraterminal (BET) proteins. Furthermore, we identified novel abemaciclib-induced neoantigens derived from allegedly non-coding genomic regions with therapeutic potential for CDK4/6i-combinational immunotherapies. Our data provide a molecular rationale for the superior efficacy of Abemaciclib in HR+ breast cancers. They also suggest that treatment with Abemaciclib could synergize with immunotherapies targeting CDK4/6i-induced tumor antigens.