Extracellular matrix-myCAF signatures correlate with resistance to neoadjuvant aPD-L1 immune checkpoint inhibition with durvalumab + metformin in HPV+ HNSCC

In HPV-positive head and neck squamous cell carcinoma (HNSCC), early resistance to neoadjuvant durvalumab plus metformin therapy is associated with baseline enrichment of extracellular matrix–associated myofibroblastic cancer-associated fibroblasts (ECM-myCAF) within the tumor compartment. In contrast, treatment responders exhibit a distinct tumor microenvironment marked by baseline enrichment of Langerhans-like dendritic cells and post-treatment upregulation of antigen presentation pathways. These findings highlight the tumor-stroma interface as a key determinant of immunotherapy response and provide a foundation for biomarker-driven patient selection. Identifying stromal and immune signatures predictive of response to neoadjuvant aPD-L1 therapy supports future strategies targeting the tumor microenvironment to improve outcomes in HNSCC.