CDK4/6 inhibitor ribociclib and doxorubicin combination treatment inhibits breast cancer bone metastasis and enhances T-cell targeted therapy.

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy, specifically aromatase inhibitors or selective estrogen receptor degraders or modulators, have significantly improved outcomes for advanced estrogen receptor-positive (ER+) breast cancer; however, therapeutic resistance remains a primary cause of mortality. Overcoming CDK4/6i treatment resistance is an urgent problem. Here, we demonstrate in ER+ PyMT-BO1 and triple-negative 4T1 murine models that ribociclib (LEE011) monotherapy reduces primary mammary fat pad (MFP) tumor burden through a mechanism partially dependent on CD8+ T cell function. However, LEE011 monotherapy fails to decrease tumor burden in bone colonization models, indicating site-specific resistance within the bone microenvironment. We identified doxorubicin as a synergistic partner that, when combined with LEE011, inhibits tumor cell proliferation and suppresses myeloid-specific arginase 1 (ARG1) expression. While doxorubicin monotherapy reduces tumor burden, its efficacy in bone is often compromised by off-target bone loss and pro-metastatic TGF-β signaling. Notably, the combination of LEE011 and doxorubicin successfully reduces bone metastatic burden, reverses treatment-induced osteoclast activity, and decreases the infiltration of ARG1+ immunosuppressive myeloid cells. Furthermore, this combination therapy remodels the bone niche to significantly enhance the efficacy of adoptive T cell immunotherapy. Collectively, these results suggest that the synergy between CDK4/6i and doxorubicin represents a promising therapeutic strategy to overcome the protective signals of the bone microenvironment in metastatic breast cancer.