NK Cell Activation by Platinum Boosts Immunotherapy in HR ⁺ /HER2 ⁻ Breast Cancer

Immunotherapy revolutionizes cancer therapeutics but shows limited efficacy in hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) breast cancer. By leveraging large-scale multi-omics and single-cell RNA sequencing (scRNA-seq), we characterize the tumor microenvironment of HR⁺/HER2^- breast cancer, revealing that an abundance of activated natural killer (NK) cells correlates with favorable anti-PD-(L)1 responses. Our preclinical models demonstrate that immunotherapy enhances NK cell cytotoxicity and immunomodulatory functions, thereby impeding tumor growth. Furthermore, drug screening of cell lines and patient-derived tumors reveals that platinum enhances NK cell cytotoxicity, potentially via the NF-κB pathway, creating synergy with immunotherapy. Consistent with these findings, a clinical cohort analysis shows an increased proportion of activated NK cells in tumors following platinum-based chemotherapy. Collectively, our study establishes the critical role of NK cells in mediating immunotherapy response in HR⁺/HER2^- breast cancer and uncovers a novel mechanism whereby platinum agents augment immunotherapeutic efficacy, offering a promising combination strategy.