Spatiotemporal-Controlled Nanoagonists Triggered STING Activation for Cascade-Amplified Photothermal Metalloimmunotherapy

Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by rapid disease progression and a high risk of metastasis. The advent of immunotherapy has revolutionized the treatment paradigm for breast cancer. Herein, a manganese-based nanoagonist (FA-IR780/EGCG@MnO₂) featuring mitochondrial targeting and photothermal therapy (PTT) was constructed for STING activation and photothermal metalloimmunotherapy. The engineered FA-IR780/EGCG@MnO₂ was constructed to enable the generation of mitochondria-targeted reactive oxygen species under laser irradiation to release mitochondrial DNA (mtDNA) and induce immunogenic cell death. The released mtDNA, as an endogenous danger-associated molecular pattern, could activate the STING pathway. Concurrently, Mn²⁺ further enhanced the activation of the STING pathway. By combining the synergistically enhanced the activation of the STING pathway, the engineered nanoagonist facilitated the DC maturation and T lymphocyte infiltration, resulting in long-term immune memory to inhibit tumor growth. This study revealed the potential combination of metalloimmunotherapy and PTT for rational regulation of the immune microenvironment.