Oncogenic EGFR rewires STING-TBK1 signalosomes to license DNA damage tolerance in NSCLC.

EGFR hotspot mutations (mEGFR), including primary L858R, exon 19 deletion, and secondary T790M, are pivotal oncogenic drivers in human non-small cell lung cancer (NSCLC). At the same time, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized tumor cell-intrinsic mechanism in which mutant EGFR (mEGFR) exploits innate immune signaling via the cGAS-STING-TBK1 pathway to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly associates with STING signalosomes and phosphorylates STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 and establishing an unexpected kinase loop critical for DNA damage repair. Genetic or pharmacological disruption of mEGFR-STING-TBK1 coupling sensitizes resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin suppressed mEGFR-driven tumors in murine models of spontaneous and immunocompetent NSCLC and in patient-derived organoids. Our findings suggest a new function of cGAS-STING in DNA damage tolerance, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.