Self-Assembled Cationic Phthalocyanine Nanophotosensitizer Drives Hypoxia-Tolerant Photodynamic Immunotherapy for HCC.

BACKGROUND: Photodynamic therapy (PDT) eliminates malignancies through spatially controlled reactive oxygen species (ROS) generation and has achieved clinical success in localized tumors. Nevertheless, its therapeutic potential is severely restricted by the poor aqueous solubility, suboptimal ROS generation efficiency, and oxygen dependency of conventional photosensitizers. To address these limitations, we developed cationic silicon phthalocyanine nanoparticles (c-SPNPs) by self-assembling morpholine-modified silicon phthalocyanine, which significantly improves aqueous solubility. RESULTS: Unlike conventional oxygen-dependent Type II PDT, c-SPNPs work primarily through Type I photochemical mechanism, generating ROS with reduced oxygen consumption. Mechanistically, c-SPNP-mediated PDT induces immunogenic cell death (ICD) in hepatocellular carcinoma (HCC) cells, as evidenced by the release of damage-associated molecular patterns (DAMPs), including surface-exposed calreticulin (CRT), extracellular ATP and HMGB1. These DAMPs promote dendritic cell maturation and enhance CD8+ T-cell infiltration within the tumor microenvironment. In murine HCC models, c-SPNP-mediated PDT effectively suppressed tumor growth while eliciting systemic antitumor immunity. CONCLUSION: Our study establishes c-SPNPs as a multifunctional nanoplatform that synergizes oxygen-efficient PDT and immunotherapy, offering a promising strategy for hypoxic solid tumor treatment.