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

Chemotherapeutic drugs, either alone or in combination with immunotherapy, are routinely used in cancer treatment. However, cancer cells frequently develop resistance to chemotherapy, and the underlying mechanisms remain incompletely understood. Using head and neck squamous cell carcinoma as a model, we show that chemotherapy activates the cGAS-STING pathway, leading to the induction of TNF. TNF mediates a paracrine signalling pathway in recipient tumour cells, leading to IKKβ activation and ATG9A phosphorylation at serine 654, thereby promoting autophagy. Moreover, IKKβ activation and ATG9A S654 phosphorylation are induced by TNF, nutrient deprivation and mTOR inhibition, suggesting that the IKKβ-ATG9A axis may represent a common regulatory mechanism of autophagy. Analysis of patient samples further reveals that chemotherapy induces autophagy, and elevated phosphorylation of ATG9A at S654 correlates with poor chemotherapy response. Of note, TNF blockade enhances therapeutic efficacy in both chemotherapy alone and chemotherapy combined with immune checkpoint inhibition. Together, our findings uncover a previously unrecognized TNF-IKKβ-ATG9A signalling axis that promotes autophagy and highlight TNF blockade as a promising strategy to overcome chemotherapy resistance.