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

  • Cell Death Discov. 2025 Jul 22;11(1):337. doi: 10.1038/s41420-025-02627-1.
Sijia Liu  #  1 ,  Binle Tian  #  2  3 ,  Na Wang  4 ,  Zhilong Wang  5 ,  Wen Zhang  5 ,  Qi Li  6  7 ,  JianFei Wang  8  9 ,  Guo-Huang Fan  10 ,  Caicun Zhou  11  12
Affiliations
  • 1. Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2. Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3. Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. Department of Antibody Development, Immunophage Biotech Co., Ltd, Shanghai, China.
  • 5. Department of Oncology, Immunophage Biotech Co., Ltd, Shanghai, China.
  • 6. Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 7. Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 8. Executive Office, Immunophage Biotech Co., Ltd, Shanghai, China. [email protected].
  • 9. Shanghai Laboratory Animal Research Center, Shanghai, China. [email protected].
  • 10. Executive Office, Immunophage Biotech Co., Ltd, Shanghai, China. [email protected].
  • 11. Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • 12. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40695812 DOI: 10.1038/s41420-025-02627-1
Abstract

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.

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