CDK4/6 Inhibition Induces CD8 ⁺ T Cell Antitumor Immunity via MIF‐Induced Functional Orchestration of Tumor‐Associated Macrophages

Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression from the G₁ to S phase. Recently, CDK4/6 inhibition (CDK4/6i) is demonstrated to enhance antitumor immunity, as evidenced by increased tumor infiltration of CD8⁺ T cells; however, the mechanism underlying this phenomenon remains unclear. This study reveals that CDK4/6i enhances intratumoral CD8⁺ T cell infiltration in breast tumors through functional reprogramming of tumor-associated macrophages (TAMs), facilitating indirect interactions between tumor and CD8⁺ T cells. Mechanistically, CDK4/6i enhances the accumulation and activation of M1 TAMs and promotes the M2 to M1 polarization via augmented interaction of the macrophage migration inhibitory factor (MIF)-CD44/CD74 axis between tumor cells and macrophages. CDK4/6i drives tumor cells to secrete MIF by activating the HIF-1α pathway. CDK4/6i-trained M1 TAMs increase the population of CD8⁺ T cells and activate them through the MHC-I antigen presentation machinery. Inhibition of MIF or loss of Mif in tumor cells reverses the immunostimulatory effects of CDK4/6i on macrophages and subsequent CD8⁺ T cell antitumor immunity. Therefore, CDK4/6i-trained M1 TAM supernatant therapy surmounts the immunosuppressive tumor microenvironment and induces a tumor response to low-dose PD-1 immune checkpoint blockade therapy in breast cancers.