Platinum-Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment

  • Angew Chem Int Ed Engl. 2023 Jan 9;62(2):e202213337. doi: 10.1002/anie.202213337.
Tao Yang  1  2 ,  Shuren Zhang  1  2 ,  Hao Yuan  1 ,  Ying Wang  3 ,  Linxiang Cai  3 ,  Hanhua Chen  3 ,  Xiaoyu Wang  1 ,  Dongfan Song  1 ,  Xiaohui Wang  4 ,  Zijian Guo  1  2 ,  Xiaoyong Wang  3
Affiliations
  • 1. State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.
  • 2. Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing, 210023, P. R. China.
  • 3. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, P. R. China.
  • 4. Institute of Chemical Biology and Functional Molecules, State Key Laboratory of Materials-Oriented Chemical Engineering, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, 211816, P. R. China.
PMID: 36259513 DOI: 10.1002/anie.202213337
Abstract

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key pro-tumorigenic marker of tumor-infiltrating macrophages, showing potent immunosuppressive activity in tumor microenvironment. A platinum(IV) complex OPA derived from oxaliplatin (OP) and artesunate (ART) exhibited direct cytotoxicity against human colon Cancer cells and immunomodulatory activity to inhibit TREM2 on macrophages in vitro and vivo. Furthermore, OPA deterred the tumor growth in mouse models bearing MC38 colorectal tumor by reducing the number of CD206+ and CX3 CR1+ immunosuppressive macrophages; it also promoted the expansion and infiltration of immunostimulatory dendritic, cytotoxic T, and natural killer cells. OPA is the first small-molecular TREM2 inhibitor capable of relieving immunosuppressive tumor microenvironment and enhancing chemical Anticancer efficiency of a platinum drug, thus showing typical characteristics of a chemoimmunotherapeutic agent.

Keywords
TREM2 inhibitor; chemoimmunotherapeutic agent; immunosuppression; platinum drug; tumor microenvironment.
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