Nociceptive neurons protect cancer cells against oxidative stress.

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.