Photodynamic therapy in head and neck squamous cell carcinoma: immunomodulation and stromal targeting of cancer-associated fibroblasts

Head and neck squamous cell carcinoma (HNSCC) remains challenging due to its complex tumor microenvironment (TME) and resistance to conventional treatments. Within this context, cancer-associated fibroblasts (CAFs) play a central role in stromal remodelling and immune evasion. Photodynamic therapy (PDT) employs a photosensitizer (PS) activated by light to generate reactive oxygen species (ROS), inducing direct cytotoxicity and immunogenic cell death (ICD). Conventional PS achieve high local control in early-stage or superficial HNSCC but are limited by hypoxia, stromal stiffness, and restricted light penetration. Nanoparticle-based PS improve tumor and stromal targeting, modulate CAF activity, normalize the extracellular matrix (ECM), and facilitate immune infiltration. PDT-induced ICD activates dendritic cells (DCs) and primes CD8⁺ T cells, linking local tumor killing with systemic immune activation. Despite limited clinical evidence, future translational studies are warranted to investigate CAF-targeted PDT combined with standard therapies to remodel the immunosuppressive TME and improve clinical outcomes in HNSCC.