MARCO expression on myeloid-derived suppressor cells is essential for their differentiation and immunosuppression.

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.