Amplifying Anti‐Tumor Immune Responses via Mitochondria‐Targeting Near‐Infrared Photodynamic Therapy

Pro-inflammatory photodynamic therapy (PDT) holds immense potential to ignite robust and long-lasting systemic anti-tumor immune responses. However, the limited penetration depth of conventional ultra violet (UV)-visible irradiation and the tumor hypoxia microenvironment significantly constrain the efficacy of immune-regulatory PDT. Here, a mitochondria-targeting enhanced nanoplatform (NZ_@TG) is reported, activated by near-infrared (NIR) light-driven PDT, to address these challenges and amplify systemic anti-tumor immunity. This nanoplatform employs an interfacial lanthanide-organic triplet photosensation mechanism to realize localized oxidative damage of oxygen-rich mitochondria under NIR irradiation. Simultaneously, the exacerbated hypoxia induced by PDT activates a TH302 prodrug, resulting in cell cycle arrest in highly proliferative tumor cells. These combined effects trigger immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) to activate immune responses. This approach demonstrates significantly enhanced tumor ablation in deep-seated lesions in orthotopic liver tumor models and induces long-term anti-tumor immune memory. Moreover, the NIR-PDT-induced immune activation markedly improves the immune checkpoint blockade (ICB) therapy efficacy. This strategy offers a robust modality for immune activation in cancer therapy, paving the way for effective treatment of deep-seated tumors and preventing recurrence.