Liu Sijia, Tian Binle, Wang Na, Wang Zhilong, Zhang Wen, Li Qi, Wang JianFei, Fan Guo-Huang, Zhou Caicun
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Discov. 2025 Jul 22;11(1):337. doi: 10.1038/s41420-025-02627-1.
Myeloid-derived suppressor cells (MDSCs) significantly contribute to the immunosuppressive tumor microenvironment (TME), and targeted inhibition of MDSCs is a potential therapeutic strategy against cancer. Here, we identify macrophage receptor with collagenous structure (MARCO) as a critical regulator of MDSC differentiation and immunosuppression in breast cancer. The present study demonstrates that MARCO is expressed on MDSCs, and breast tumor-derived exosomes (TDEs) enriched with macrophage migration inhibitory factor (MIF) promote MDSC differentiation and amplify immunosuppressive activity by up-regulating MARCO. Genetic ablation of MARCO in a murine breast cancer model attenuated tumor growth, accompanied by reduced monocytic MDSCs (M-MDSCs) and total tumor-associated macrophages (TAMs), along with enhanced infiltration of CD8 T cells and natural killer (NK) cells. Furthermore, we developed a specific MARCO down-regulation-promoting monoclonal antibody that impeded TDE-induced MDSC differentiation and immunosuppression. In vivo, MARCO down-regulating antibody suppressed tumor growth and reprogrammed the TME by diminishing immunosuppressive MDSCs and TAMs and revitalizing CD8 T cells and NK cells. Strikingly, combining the MARCO down-regulating antibody with PD-1 blockade synergistically enhanced anti-tumor efficacy. This work establishes MARCO as a key regulator of MDSC-mediated immunosuppression and presents a compelling case for the inclusion of MARCO as a therapeutic target in cancer immunotherapy.
髓系来源的抑制性细胞（MDSCs）对免疫抑制性肿瘤微环境（TME）有显著贡献，靶向抑制MDSCs是一种潜在的抗癌治疗策略。在此，我们确定具有胶原结构的巨噬细胞受体（MARCO）是乳腺癌中MDSC分化和免疫抑制的关键调节因子。本研究表明，MARCO在MDSCs上表达，富含巨噬细胞迁移抑制因子（MIF）的乳腺肿瘤衍生外泌体（TDEs）通过上调MARCO促进MDSC分化并增强免疫抑制活性。在小鼠乳腺癌模型中对MARCO进行基因敲除可减缓肿瘤生长，同时单核细胞MDSCs（M-MDSCs）和肿瘤相关巨噬细胞（TAMs）总数减少，CD8 T细胞和自然杀伤（NK）细胞浸润增加。此外，我们开发了一种促进MARCO下调的特异性单克隆抗体，该抗体可阻止TDE诱导的MDSC分化和免疫抑制。在体内，下调MARCO的抗体可抑制肿瘤生长，并通过减少免疫抑制性MDSCs和TAMs以及恢复CD8 T细胞和NK细胞的活力来重新编程TME。引人注目的是，将下调MARCO的抗体与PD-1阻断联合使用可协同增强抗肿瘤疗效。这项工作确立了MARCO作为MDSC介导的免疫抑制的关键调节因子，并有力地证明了将MARCO纳入癌症免疫治疗的治疗靶点。
