Immunogenic cell death (ICD) is a regulated cell death that stimulates the immune responses resulting in the establishment of longterm immunological memory. ICD alert the immune system by tumor-associated antigens and tumor neoantigens (i.e., antigenicity) and releasing immunostimulant mediators such as the damage- associated molecular patterns (DAMPs, adjuvanticity). ICD can be efficiently induced by photodynamic therapy (PDT). Our key hypothesis is that PDT based on clinically approved and in-house developed photosensitizers, which are efficient in several murine cancer models, will induce ICD in head and neck squamous cell carcinomas (HNSCCs) which are the fourth most frequent types of cancer in men. Specifically, we aim to demonstrate for the first time that PDT will modulate the immunogenicity of dying HNSCC cells not only by releasing DAMPs but also by increasing antigenicity of dying HNSCC cells by affecting their landscape of antigens. This will lead to the activation of the innate and adaptive immune system and to the improvement of anti-cancer therapy of HNSCC patients. For the study, we will exploit HNSCC cells derived from patients’ biopsies, representing an ideal preclinical model that incorporates heterogeneity of tumors observed in patients. In this way, we will obtain the data required to support future clinical trials based on PDT. Indeed, the ultimate goal of the neoantigen identification is to pave the way for developing patient-specific targeted vaccine therapies.