Photodynamic immunotherapy with checkpoint inhibitor-loaded nanogels: A synergistic frontier in cancer nanomedicine.

Advances in nanogel engineering have ushered in a new era of precision immunotherapy by enabling the coordinated delivery of photosensitizers and immune checkpoint inhibitors (ICIs) in solid tumors. This review examines the mechanistic and translational foundations of photodynamic immunotherapy (PDI) using checkpoint inhibitor-loaded nanogels, emphasizing innovations that overcome longstanding challenges such as immune resistance, tumor heterogeneity, and systemic toxicity. Nanogels are critically evaluated in the context of competing nanoparticle platforms, with a focus on how their physicochemical structure, defined at the nanoscale, enables spatiotemporal control over therapeutic activation. Strategies for enhancing intratumoral specificity, co-delivery efficiency, and sequential release of immunomodulators are explored, alongside the emerging role of stimuli-responsive materials and biomimetic coatings. Key biological mechanisms are delineated, including ROS-mediated immunogenic cell death (ICD), T cell reinvigoration, and tumor microenvironment remodeling. The review further addresses barriers to clinical translation, ranging from immunotoxicity and dosimetry to regulatory classification, and proposes integrated solutions via AI-driven design, personalized biomarkers, and multimodal delivery platforms. Concluding with a forward-looking perspective, this article outlines a design and implementation roadmap for next-generation nanogels capable of transforming PDI into a safe, adaptable, and patient-specific therapeutic modality.