A novel hypocrellin B derivative for photodynamic therapy-driven cancer immunotherapy via triggering immunogenic cell death

The natural photosensitizer hypocrellin B (HB) exhibits restricted absorption within the 650–900 nm therapeutic window thereby impeding its clinical translation. This work synthesizes chemical derivative (HB1) from HB to address its restricted therapeutic-window absorption. Upon 660 nm laser irradiation, HB1 localizes to lysosomes, inducing membrane permeabilization and immunogenic cell death (ICD) while concurrently enhancing dendritic cell (DC) maturation and phagocytosis in vitro through photodynamic therapy (PDT). By further co-encapsulating HB1 and the immunoadjuvant R837 in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, HB1 induces ICD to release tumor antigens that synergize with R837-mediated immune stimulation, achieving potent antitumor effects via enhanced CD8⁺/CD4⁺ T cell infiltration and DC activation. Furthermore, prophylactic administration of PDT-generated tumor lysates combined with R837 primes antitumor immunity and delays tumor progression. These results substantiate the clinical potential of HB1 for photodynamic immunotherapy and suggest a promising strategy for developing personalized PDT vaccines against tumor recurrence. The approach leverages surgically resected tumor tissues to prepare tumor-specific vaccines, providing insights for clinical translation in cancer immunotherapy.