IL-1-mediated inflammation promotes metastatic dissemination and resistance to EGFR-targeted therapy.

Resistance to anti-EGFR therapy remains a major challenge in head and neck squamous cell carcinoma (HNSCC), as adaptive mechanisms driven by drug-tolerant persister cells (DTPs) ultimately compromise treatment efficacy. Here, we identify Interleukin-1 (IL-1)-mediated inflammation as a critical driver of resistance to the anti-EGFR monoclonal antibody cetuximab (CTX). Through meta-analysis of HNSCC patient datasets stratified by lymph node status, together with in vitro studies using sensitive and CTX-resistant HNSCC cell lines and in vivo nude mouse models, we demonstrate that IL-1 in the tumor microenvironment reduces EGFR degradation, thereby promoting receptor stability and therapeutic escape. In sensitive cells, CTX suppresses the IL-1 pathway via direct transcriptional downregulation of IL-1α and IL-1β; however, this regulatory effect is lost in resistant cells, where a sustained IL-1-driven pro-inflammatory program enhances invadopodia formation, proliferation, and metastatic potential. Importantly, pharmacological inhibition of IL-1 in mice restored sensitivity to anti-EGFR therapy and prevented lung metastatic dissemination of resistant cells. These findings uncover an inflammatory axis underlying resistance and suggest that targeting IL-1 may improve EGFR-targeted therapies and limit metastatic spread in HNSCC.