Abstract

How cancer cells exploit the tumor microenvironment (TME) to alleviate oxidative stress remains largely unclear. Here, we show that nociceptive neurons, via secretion of epiregulin, increase Lnc-GCLC-1 expression in cancer cells, thereby protecting them against oxidative stress-induced cell death in head and neck squamous cell carcinoma (HNSCC). Specifically, nociceptive neurons increase Ets variant 4 (ETV4)-mediated Lnc-GCLC-1 expression in cancer cells upon oxidative stress. Increased cellular Lnc-GCLC-1 interacts with and ubiquitinates Kelch-like ECH-associated protein 1 (KEAP1), leading to disruption of the KEAP1-NRF2 interaction and subsequent activation of the NRF2 signaling pathway. This enhances GSH biosynthesis in cancer cells and protects them against cisplatin-induced oxidative stress. Targeting nociceptive neurons or the EREG-Lnc-GCLC-1-NRF2 axis therefore improves the therapeutic efficacy of cisplatin. Moreover, high Lnc-GCLC-1 levels correlate with poor prognosis in patients with HNSCC. Our study sheds light on nociceptive neurons as accomplices that assist HNSCC cells in surviving oxidative stress.