The E3 ubiquitin ligase RFWD3 binds the exonuclease TREX1 and protects it from TRIM24‐mediated ubiquitination and degradation, leading to the eradication of intracellular dsDNA, inhibition of the cGAS‐STING pathway, and immunosuppressive microenvironment of lung cancer. Here, RFWD3 is linked to lung carcinoma.