5‐ALA mediated photodynamic therapy increases natural killer cytotoxicity against oral squamous cell carcinoma cell lines

Abstract Oral squamous cell carcinoma (OSCC) constitutes over 90% of oral cancers, known for its aggressiveness and poor prognosis. Photodynamic therapy (PDT) has emerged as a promising adjuvant therapy and is linked to immunogenic cell death, activating innate and adaptive anti‐tumor responses. Natural Killer (NK) cells, key players in malignant cell elimination, have not been extensively studied in PDT. This study evaluates whether PDT increases OSCC cell lines' susceptibility to NK cell cytotoxicity. PDT, using 5‐aminolevulinic acid (5‐ALA) and LED irradiation, was applied to Ca1 and Luc4 cell lines. Results showed a dose‐dependent viability decrease post‐PDT. Gene expression analysis revealed upregulation of NK cell‐activating ligands (ULBP1‐4, MICA/B) and decreased MHC class I expression in Ca1, suggesting increased NK cell susceptibility. Enhanced NK cell cytotoxicity was confirmed in Ca1 but not in Luc4 cells. These findings indicate that PDT may enhance NK cell‐mediated cytotoxicity in OSCC, offering potential for improved treatment strategies.