STING-dependent TNF signalling promotes IKKβ-mediated ATG9A phosphorylation and autophagy.

In head and neck squamous cell carcinoma, chemotherapy activates cGAS–STING to induce TNF, which triggers IKKβ activation and ATG9A phosphorylation at serine 654, promoting autophagy.

• Why it matters: Chemotherapy resistance in cancer is incompletely explained, and the study targets a gap in how drug-induced innate sensing and TNF signaling regulate autophagy in tumor cells.
• What they did: Using a head and neck squamous cell carcinoma model, the work links TNF to paracrine IKKβ activation and ATG9A S654 phosphorylation, and tests induction by nutrient deprivation and mTOR inhibition.
• The result: Patient-sample analysis shows chemotherapy induces autophagy and that elevated ATG9A S654 phosphorylation correlates with poor chemotherapy response; TNF blockade improves efficacy with chemotherapy alone or combined with immune checkpoint inhibition.

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