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

ABSTRACT: Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression from the G1 to S phase. Recent findings have demonstrated that CDK4/6 inhibition (CDK4/6i) enhances antitumor immunity, as evidenced by increased tumor infiltration of CD8+ T cells, though the underlying mechanism remains unclear. Our current study reveals that CDK4/6i enhances intratumoral CD8+ T cell infiltration in breast tumors through the functional reprogramming of tumor-associated macrophages (TAMs), facilitating indirect interactions between tumor cells and CD8+ T cells. Mechanistically, CDK4/6i enhances the proliferation and activation of M1 macrophages and promote the polarization of M2 to M1 macrophages via the macrophage migration inhibitory factor (MIF)-CD44/CD74 axis between tumor cells and macrophages. CDK4/6i-trained M1 TAMs increase and activate CD8+ T cells through MHC-I antigen presentation machinery. Inhibition of MIF in tumor cells or loss of MIF 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 invokes a tumor response to low-dose PD-1 immune checkpoint blockade therapy in breast cancers.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow, Macrophage

SUBMITTER: lin yang  

LAB HEAD: Chuxia Deng

PROVIDER: PXD057791 | Pride | 2026-06-29

REPOSITORIES: Pride