Light Metabolically Reprograms CD8 + T Cells to Potentiate STING‐Driven Tumor Eradication and Prevent Metastasis

Abstract Immunotherapy remains ineffective in many solid tumors due to poor T‐cell infiltration and a metabolically suppressive tumor microenvironment. A dual strategy combining low‐level light (LLL) therapy with a nanoscale stimulator of interferon genes (STING) agonist formulation (nanoSTING@Mn) is presented to enhance immune activation and metabolic fitness for durable tumor immunity against T‐cell lymphoma (EL4) model. NanoSTING@Mn, composed of ADU‐S100 complexed with Mn 2 ⁺ and encapsulated in biomimetic liposomes, potently activates the cGAS–STING pathway, induces a type I interferon response, and promotes lymphocyte infiltration. These monocytes polarize into M1 macrophages, suppressing regulatory T cells. Simultaneously, LLL photo‐biomodulation reprograms mitochondrial metabolism in tumor‐infiltrating CD8⁺ T and natural killer cells, restoring their durability and leading to complete local tumor eradication. This combination expands a distinct CD8⁺ T‐cell subset with Tcf‐1 ⁺ progenitor‐exhausted features and elevated memory/effector gene expression, enhancing proliferation and cytotoxicity, as shown by single‐cell RNA sequencing. Intranasal nanoSTING@Mn delivery mobilizes these LLL‐revived T cells to the lung, where they differentiate into resident memory T cells and establish systemic antitumor immunity. Upon intravenous rechallenge, disseminated tumor cells are eliminated, preventing metastasis and ensuring long‐term protection. This synergistic approach offers a scalable platform to boost immunotherapy efficacy and redefines immune‐based metastasis prevention strategies.