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

Abstract 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.