An Immunogenic Cell Death-Enhanced Self-Assembled Nanoparticle-Composite Hydrogel for Postoperative Local Immunotherapy of Melanoma.

Abstract

Photodynamic therapy (PDT) can elicit antitumor immunity by inducing immunogenic cell death (ICD), making it an attractive option for postoperative local cancer treatment. However, in solid tumors, aberrant vasculature and an immunosuppressive microenvironment often restrict immune-cell infiltration, thereby weakening the immune benefits of PDT. Here, we develop an ICD-amplifying, self-assembled nanoparticle-hydrogel composite (methacrylate-functionalized fucoidan hydrogel [dFuGMA]-Ce6-Tas nanoparticles [CTNPs]) for local immunotherapy following melanoma resection. In this system, the photosensitizer chlorin e6 and the immunomodulatory/antiangiogenic agent tasquinimod (Tas) spontaneously coassemble into carrier-free nanoparticles (CTNPs), which are subsequently embedded in a photocrosslinkable dFuGMA to enable in situ gelation and coordinated therapy at the surgical site. In vitro, CTNPs markedly enhanced cellular uptake, reactive oxygen species generation, and ICD-associated responses. In a postoperative melanoma model, dFuGMA-CTNPs combined with laser irradiation significantly suppressed tumor regrowth and promoted immune activation, as evidenced by increased dendritic cell maturation (4.6-fold) and enhanced infiltration of CD4⁺ (4.8-fold) and CD8⁺ T cells (5.8-fold). Mechanistically, Tas induced tumor vascular normalization by downregulating the hypoxia-inducible factor 1-alpha/vascular endothelial growth factor axis, thereby synergistically potentiating PDT-triggered ICD and downstream immune responses. Transcriptomic profiling further confirmed modulation of pathways associated with "immune response" and "T cell activation." In conclusion, dFuGMA-CTNPs achieves a dual-pathway synergy through ICD enhancement and vascular normalization, providing a precisely localized and translationally feasible immunotherapeutic strategy to prevent postoperative melanoma recurrence.