Oxaliplatin-artesunate conjugate intensifies suppression on colorectal cancer by boosting antitumor immunity.

Immunosuppressive tumor microenvironment is the major obstacle for antitumor immunotherapy. Elimination of myeloid-derived suppressor cells (MDSCs) potentiates immunotherapy for various solid tumors. Oxaliplatin-artesunate complex OPA decreases MDSCs by inhibiting CD33 and the triggering receptor expressed on myeloid cells 2 (TREM2) in the TME, and enhancing dendritic cell maturation due to its ability to facilitate immunogenic cell death and activate the cyclic-GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Moreover, OPA upregulates the costimulatory molecule CD28 and downregulates the immune checkpoint cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells, thus impeding the T cell depletion and immunosuppression. The activation of immune circulation and immunosignal pathway increases the chemotherapeutic activity of parent oxaliplatin. In addition, OPA serves as a cancer vaccine to inhibit tumor metastasis and reoccurrence. Lastly, the stability and safety profiles are superior to that of oxaliplatin. OPA is a unique chemoimmunotherapeutic agent with a distinct mechanism of action and prominent efficacy on orthotopic colorectal cancer in mouse models.