Sandra Schmitz : Impact of the tumor environment on treatment resistance in head and neck cancer

Saturday, April 25, 2026 at 10:15 a.m. - Public session on the impact of technological advances in cancer therapy Sandra Schmitz (UCLouvain) Head and neck squamous cell carcinoma (HNSCC) is a disease with a poor prognosis, with more than half of patients with advanced stages of the disease relapsing despite multimodal treatment. In recurrent, inoperable, or metastatic forms, cetuximab (anti-EGFR) is used routinely for patients ineligible for immunotherapy, but resistance inevitably develops. No recurrent genetic alteration explains the mechanism, pointing towards non-genetic causes, particularly remodeling of the tumor microenvironment. Tumor-associated fibroblasts (CAFs) occupy a significant proportion of the tumor volume in advanced forms. Clinical studies conducted in our laboratory have shown that anti-EGFR treatment induces early recruitment of CAFs, overexpression of extracellular matrix (ECM) genes, and epithelial-mesenchymal transition in tumor cells. Using patient-derived co-culture models, we demonstrated that CAFs confer cetuximab resistance to several HNSCC cell lines. Multi-omics profiling identified ECM-remodeling myofibroblastic CAFs (ECM-myCAFs) as the key subtype for this resistance. Unexpectedly, non-tumor fibroblasts (NFs) also acquire a CAF-like phenotype upon contact with tumor cells in 3D spheroids, reproducing the resistance and providing a model for studying this transition in real time. Blocking fibroblast activation with pirfenidone, an antifibrotic agent targeting the TGF-β pathway, prevents this transition, disrupts spheroid architectural remodeling, and restores cetuximab sensitivity. These findings pave the way for a therapeutic strategy combining anti-EGFR therapy and early antifibrotic intervention to delay or prevent the emergence of resistance in HNSCC.