Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer, the most common subtype, shows a low pathological complete response (pCR) rate and limited benefit from immunotherapy, highlighting the need for more effective strategies. Although immunotherapy has become increasingly important in cancer treatment, its efficacy in this subtype remains modest. CDK4/6 inhibitors, first-line treatments for advanced HR + /HER2- breast cancer, not only suppress tumor proliferation but may also reshape the immune microenvironment, offering new opportunities for immunotherapy. In this study, multiplex immunohistochemistry, drug testing of HR + /HER2- breast cancer organoids, single-cell sequencing, and primary cell coculture showed that the CDK4/6 inhibitor palbociclib promotes fibroblast senescence, thereby increasing IGF1 and FGF7 levels. These factors drive macrophage polarization toward an M2-like phenotype through STAT3 Tyr705 phosphorylation and ARG1 upregulation, resulting in arginine depletion and reduced lymphocyte viability. To counteract this immunosuppressive microenvironment, we selected the CSF1R inhibitor pexidartinib. Pexidartinib inhibited macrophage activity, suppressed STAT3 phosphorylation, reduced ARG1 expression, and increased lymphocyte viability, thereby enhancing the antitumor efficacy of palbociclib in HR + /HER2- breast cancer. These findings reveal a previously unrecognized immunosuppressive mechanism induced by CDK4/6 inhibition and support CSF1R blockade as a promising combination strategy.
© 2026. The Author(s).