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

Federspiel J, Ferro F, Dudas J, Stenzl AK, Hofauer BG

Translational oncology, 2026

Abstract

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.

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