Smohaze‐Upregulated RFWD3 Competes with TRIM24 to Stabilize TREX1 and Reduce Cytosolic dsDNA in Non‐Small Cell Lung Cancer

The three-prime repair exonuclease 1 (TREX1), an intracellular double-stranded DNA (dsDNA) degrader that inhibits the stimulator of interferon (IFN) genes (STING) pathway, is turned over by E3 ligase TRIM24-mediated proteasomal degradation. To uncover TREX1-stabilizers in non-small cell lung cancer (NSCLC), mass spectrometry is conducted, and 374 candidates are identified, with the RING Finger and WD Repeat Domain 3 (RFWD3) as a TREX1 protector that sequesters it from TRIM24. 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. Furthermore, smoker patients have higher RFWD3 levels than non-smoker patients, and cigarette smoke extract, PM_2.5, and benzo(a)pyrene upregulatesRFWD3 via transcription factor aryl hydrocarbon receptor. These results indicate a role of RFWD3 in tobacco smoke and haze (smohaze)-promoted immune evasion, inhibition of which activates STING-IFN signaling and synergizes with immune checkpoint inhibitors in NSCLC.