Hypoxia-responsive oncolytic conjugate triggers type-II immunogenic cell death for enhanced photodynamic...

Immunogenic cell death (ICD) induced by photodynamic therapy (PDT) holds great promise for enhancing anti-tumor immunotherapy; however, its clinical efficacy is often hampered by suboptimal ICD induction and the exacerbation of an immunosuppressive tumor microenvironment (TME) following PDT. Herein, we present a tumor-targeted and hypoxia-responsive peptide-photosensitizer conjugate, A6-dMP-VP, which integrates an oncolytic peptide (dMP) with a CD44-targeting motif (A6), hypoxia-responsive groups, and the photosensitizer verteporfin (VP). Following systemic administration, A6-dMP-VP preferentially accumulates in 4T1 tumors, where the hypoxic TME triggers its response. Remarkably, the combined oncolytic activity and PDT effect of A6-dMP-VP effectively induce type-II ICD via mitochondrial disruption and endoplasmic reticulum stress, leading to robust antigen release. This process significantly enhances dendritic cell maturation and cytotoxic T cell priming, ultimately achieving potent suppression of both primary and metastatic tumors. Our findings establish A6-dMP-VP as a highly effective type-II ICD inducer, offering a novel strategy to overcome the limitations of PDT and advance photodynamic-oncolytic immunotherapy.