Overexpression of RFWD3 promotes tumor growth with increased myeloid‐derived suppressor cells (MDSCs), while inhibition of RFWD3 increases intracellular dsDNA levels, activates the STING‐IFN signaling, decreases MDSCs, and enhances the efficacy of PD‐L1 blockade in murine NSCLC models. Here, RFWD3 is linked to non-small cell lung carcinoma.