Advances in Nanotechnology-Driven Enhancement of Type I Photosensitizers for Tumor Photo-Immunotherapy

The integration of photodynamic therapy (PDT) with immunotherapy (photo-immunotherapy, PIT) has emerged as a promising strategy for improving cancer treatment outcomes. Unlike oxygen-dependent type II PDT, electron-transfer-driven type I PDT generates a diverse spectrum of reactive oxygen species (ROS), including superoxide anion and hydroxyl radicals. These radicals induce stronger oxidative stress, promote the release of tumor-associated antigens, and trigger damage-associated molecular patterns. Such effects offer potential advantages under the hypoxic conditions that are common in solid tumors. However, small-molecule photosensitizers still face intrinsic drawbacks, including rapid systemic clearance, limited tumor accumulation, and weak immunogenicity. These limitations remain formidable obstacles to clinical application. To enhance therapeutic efficacy and immune-stimulatory potential, a variety of nanomaterials have been engineered. In this context, a comprehensive overview of recent advances in nanomaterial-based type I PIT is both timely and essential. This review summarizes progress in this area, emphasizing design strategies, ROS generation mechanisms, and immunomodulatory effects. It also discusses key clinical transformation challenges and future directions to guide the rational design of next-generation PIT nanoplatforms. Collectively, these advances highlight promising opportunities for more effective and selective nanotechnology-driven strategies, while further research is required to evaluate their clinical potential.