Autophagy hub genes mediate photodynamic therapy tolerance in nasopharyngeal carcinoma through cytoprotective autophagy and survival signaling

Photodynamic therapy (PDT) offers a promising treatment option for nasopharyngeal carcinoma (NPC); however, intrinsic and adaptive resistance remains a major clinical limitation. Autophagy has emerged as a key cytoprotective mechanism in therapy resistance, yet the critical regulatory nodes governing PDT responses in NPC are incompletely defined. A curated set of 1206 autophagy-related genes from the Human Autophagy Database (HADb) was analyzed using STRING and Cytoscape to identify central hub genes. NPC cell lines C666-1 and HONE1 were treated with 5-aminolevulinic acid (5-ALA)–mediated PDT alone or in combination with rapamycin (autophagy activator) or chloroquine (autophagy inhibitor). Hub gene expression and autophagy-associated markers were evaluated by RT-qPCR and western blotting, including LC3B and p62/SQSTM1. Functional consequences were assessed using cell viability, colony formation, and migration assays. In addition, siRNA-mediated knockdown of key hub genes was performed to genetically validate their functional roles in PDT responses. Network analysis identified AKT1, BECN1, BCL2, and ATG5 as central hubs within the autophagy interactome. PDT induced the expression of these genes and activated an autophagy-associated survival program, which was further enhanced by rapamycin and suppressed by chloroquine. Genetic depletion of ATG5 or BECN1 significantly reduced basal clonogenic survival and markedly sensitized NPC cells to PDT, confirming their essential role in autophagy-dependent cytoprotection. Multi-omics analyses revealed low mutation frequencies but prominent promoter hypomethylation and elevated expression of hub genes in NPC, which correlated with poor prognosis, altered immune infiltration patterns, and differential drug sensitivity profiles. Collectively, these findings demonstrate that AKT1, BECN1, BCL2, and ATG5 constitute a core autophagy-driven survival axis that limits PDT efficacy in NPC. Pharmacologic and genetic disruption of this pathway effectively enhances PDT sensitivity, highlighting autophagy inhibition as a rational strategy to overcome therapeutic resistance in NPC.