Targeting CDK4/6 potentiates the efficacy of anti-CD47 therapy via modulating the suppressive function of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are key regulators of immunological responses in tumor microenvironment (TME), exerting a profound impact on cancer progression. The current study aimed to explore TAMs-targeted strategies designed to overcome the immunosuppressive effects and restore antitumor immunity. Our findings demonstrated that selective CDK4/6 inhibitors promote the polarization of M2 macrophages toward the M1 phenotype, which was validated in both in vitro experiments and preclinical tumor models. Concurrently, CDK4/6 inhibitors significantly enhanced the phagocytic capacity of macrophages and activated effector T cell-mediated immune responses. Mechanistically, CDK4/6 inhibitors reduced p53 levels by altering p53 mRNA expression and facilitating its protein degradation. Furthermore, CDK4/6 inhibitor combined with CD47 blockade represents a promising strategy suppressing breast cancer growth. Taken together, our findings unveil a previously unappreciated antitumor mechanism mediated by CDK4/6 inhibition and propose a novel macrophage-based breast cancer immunotherapeutic approach.