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

作者：Lin He, Yuzhong Peng, Lat‐lun Leong, Jingbo Zhou, Dongyang Tang, Weilu Wang, Xiaoran Wu, Josh Haipeng Lei, Yongqin Ye, Yangyang Feng, Yunfeng Qiao, Xiangpeng Chu, Di Mu, Qi Zhao, Tzu‐Ming Liu, Yan Chen, Paul Kwong Hang Tam, Chu‐Xia Deng · 发表于：Advanced Science · 年份：2025 · DOI：10.1002/advs.202511330 · 被引用次数：6 · 研究领域：Macrophage Migration Inhibitory Factor、Education and Character Development

Abstract Cyclin‐dependent kinases 4 and 6 (CDK4/6) regulate cell cycle progression from the G 1 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.