Oncogenic EGFR rewires STING-TBK1 immune machinery to license DNA damage tolerance

Abstract

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). Meanwhile, NSCLC resistance to third-generation tyrosine kinase inhibitors (TKIs) is a major clinical challenge and remains mechanistically unresolved. Here, we uncover a previously unrecognized immunological mechanism whereby mEGFR exploits cGAS-STING innate immune signaling, conventionally regarded as tumor-suppressive, to sustain oncogenic signaling and therapeutic resistance. Mechanistically, mutant EGFR kinase aberrantly incorporates into STING signalosomes, directly phosphorylating STING (Y245/Y314) and TBK1 (Y577/Y677), stabilizing and hyperactivating TBK1 proteins, and establishing an unexpected and kinase loop critical for DNA damage repair. Disruption of this mEGFR-STING-TBK1 axis, genetically or pharmacologically, profoundly sensitized resistant patient-derived NSCLC organoids to chemotherapy. Combining TBK1 inhibition with cisplatin notably eradicated mEGFR-driven tumors in spontaneous and immunocompetent NSCLC murine models and patient-derived organoids. Our findings suggest a new function of cGAS-STING in the DNA damage repair program, its paradoxical exploitation by oncogenic driver mutations, and an innate immune therapeutic vulnerability in NSCLC.