CDK4/6 inhibition reprograms the breast cancer immunopeptidome via Rb-dependent chromatin and transcriptomic remodeling

The cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are standard-of-care therapies for metastatic hormone receptor-positive (HR+) breast cancer, yet their immunomodulatory effects remain underexplored. Here, we demonstrate that CDK4/6 inhibition with Abemaciclib reprograms the tumor antigen landscape by increasing major histocompatibility class I (MHC class I) presentation and reshaping the immunopeptidome in HR+ and triple-negative breast cancer cells. Through multiomics integration, we reveal that this remodeling is driven by retinoblastoma protein (Rb)-dependent transcriptional and chromatin reprogramming, reflected by increased H3K27 acetylation deposition and enhanced chromatin accessibility revealed by ATAC-seq. CDK4/6 inhibition dephosphorylates Rb, enhancing its interaction with BET family proteins and inducing chromatin remodeling that upregulates antigen-source transcripts. We identify immunogenic Abemaciclib-induced MHC class I peptides, including antigens derived from non-coding genomic regions, which can enhance tumor immunogenicity. These findings reveal a previously unrecognized role of CDK4/6is in shaping tumor antigenicity and suggest that combining CDK4/6is with immunotherapy could broaden antigenic targets in breast cancer.