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

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immunotherapy faces challenges in solid tumors due to poor T-cell infiltration and a suppressive tumor microenvironment.
• Enhancing immune activation and metabolic fitness is crucial for durable anti-tumor immunity.

Purpose of the Study:

• To investigate a dual strategy combining low-level light (LLL) therapy and a nanoscale stimulator of interferon genes (STING) agonist (nanoSTING@Mn) to improve immunotherapy efficacy.
• To enhance immune activation, metabolic fitness, and establish durable tumor immunity against T-cell lymphoma.

Main Methods:

• Developed nanoSTING@Mn using ADU-S100, Mn²⁺, and biomimetic liposomes for cGAS-STING pathway activation.
• Applied LLL therapy to reprogram mitochondrial metabolism in tumor-infiltrating CD8⁺ T and natural killer cells.
• Utilized single-cell RNA sequencing to analyze T-cell populations and gene expression.

Main Results:

• NanoSTING@Mn potently activated the cGAS-STING pathway, induced type I interferon, and promoted lymphocyte infiltration, polarizing monocytes to M1 macrophages.
• LLL therapy restored CD8⁺ T and natural killer cell durability, leading to complete local tumor eradication.
• The combination therapy expanded a CD8⁺ T-cell subset with progenitor-exhausted features, enhancing proliferation and cytotoxicity.

Conclusions:

• The synergistic approach of LLL therapy and nanoSTING@Mn enhances immunotherapy efficacy by overcoming tumor microenvironment suppression.
• Intranasal nanoSTING@Mn delivery and LLL therapy establish systemic antitumor immunity and long-term protection against metastasis.
• This scalable platform redefines immune-based metastasis prevention strategies.