Dissecting the Role of Autophagy in Photodynamic Therapy-Induced Cell Death in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with poor prognosis, and photodynamic therapy (PDT) has emerged as a promising treatment option. However, the therapeutic efficacy of PDT is strongly influenced by cellular stress-response mechanisms, particularly autophagy. This study investigated the role of autophagy in modulating NPC sensitivity to PDT using cell line models and human NPC tissue samples. Two human NPC cell lines, C666-1 and HONE1, were treated with 5-aminolevulinic acid (5-ALA, 0.5 mM, 4–6 h) followed by 405 nm light irradiation. Autophagy was pharmacologically inhibited using chloroquine (10 µM, 1 h) or activated using rapamycin (100 nM, 4 h), and genetic modulation of key autophagy-related genes was performed for mechanistic validation. In parallel, NPC tissue samples were analyzed histopathologically to evaluate PDT-associated necrosis under conditions of altered autophagy. Autophagy-related markers (ATG5, BECN1, LC3, and p62) were assessed by RT-qPCR and Western blotting with densitometric analysis. Functional assays evaluated cell viability, colony formation, and migration. Autophagy inhibition significantly enhanced PDT-induced necrosis in NPC tissues and sensitized NPC cells to PDT, resulting in reduced viability, clonogenic survival, and migratory capacity. In contrast, autophagy activation conferred cytoprotection and promoted cellular recovery following PDT. Genomic analyses revealed frequent amplification of BECN1 and LC3 in NPC, while elevated autophagy marker expression correlated with reduced immune cell infiltration. Drug sensitivity analyses further suggested that autophagy targeting may enhance responsiveness to chemotherapeutic agents. In conclusion, autophagy functions as a protective mechanism against PDT-induced damage in NPC at both cellular and tissue levels. Targeting autophagy represents a promising strategy to enhance PDT efficacy and improve therapeutic outcomes for NPC patients.