NLRC3 enhances antitumor immunity by specifically negatively regulating M-MDSCs in a STING-dependent manner

NOD-like receptor (NLR) family CARD domain containing 3 (NLRC3), an intracellular member of the NLR family, is a negative regulator of both immune cell modulation and tumor cell proliferation. However, the role of NLRC3 and the mechanisms underlying its effect on the tumor immune microenvironment remain unclear. In this study, we report that NLRC3 promotes antitumor immunity by specifically negatively regulating the infiltration and immunosuppressive function of monocytic myeloid-derived suppressor cells (M-MDSCs). Mechanistically, NLRC3 inhibits the stimulator of interferon genes (STING) signaling pathway, leading to reduced expression of programmed cell death ligand 1 (PD-L1) and CCR2 in M-MDSCs, thereby limiting the infiltration and immunosuppressive function of M-MDSCs. Notably, overexpression of NLRC3 in combination with the STING agonist c-GAMP significantly inhibited tumor growth. These findings reveal a critical role for NLRC3 in modulating the immune microenvironment and provide insights into the optimization of NLRC3-targeted therapeutics.