Nanosystem-Mediated Phototherapy (PDT/PTT) - Chemodynamic Therapy for Synergistic Antitumor Therapy: Strategies and...

Chemodynamic therapy (CDT) eradicates tumor cells by generating hydroxyl radicals (•OH) through Fenton/Fenton-like reactions, yet its therapeutic efficacy is severely constrained by intrinsic deficiencies of the tumor microenvironment (TME), including insufficient endogenous hydrogen peroxide(H₂O₂), suboptimal pH, robust glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging, and tumor hypoxia. As potent synergistic modalities, photodynamic therapy (PDT) elevates oxidative stress via ROS overproduction, while photothermal therapy (PTT) accelerates Fenton reaction kinetics and improves intratumoral nanotherapeutic penetration, collectively remedying the inherent drawbacks of single CDT. Unlike conventional reviews that primarily catalogue nanomaterial diversity and classification, this review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition. We systematically overview the core synergistic principles of integrated nanosystems, covering ROS cascade amplification, GSH depletion-initiated ferroptosis, TME acidification, extracellular matrix (ECM) degradation, and immunogenic cell death. We further summarize recent advances in dual-modal PDT-CDT, PTT-CDT, and PDT-PTT-CDT synergistic nanoplatforms, and highlight the evolutionary trend of such nanotherapeutics-from primitive thermochemical coupling designs to advanced architectures with TME-responsive targeted delivery, second near-infrared (NIR-II) deep-tissue penetration, enzyme-cascaded self-substrate supply, and integrated theranostic functions. Moreover, the key bottlenecks hindering clinical translation are discussed, including limited light penetration depth, TME heterogeneity, suboptimal biosafety profiles, and inadequate clinical validation systems. Three pivotal priorities for future translational development are further proposed: the fabrication of NIR-II deep-penetrating nanoplatforms, the establishment of standardized manufacturing and quality control workflows for regulatory compliance, and the development of TME-adaptive, imaging-guided precision tumor delivery strategies.