Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Radiotherapy (RT) can induce tumor regression beyond the irradiated area (abscopal effect).
• The precise molecular mechanisms governing the abscalcopal effect remain largely unelucidated.
• Understanding these mechanisms is crucial for developing novel cancer immunotherapies.

Purpose of the Study:

• To investigate the underlying mechanisms of the abscopal effect induced by RT.
• To explore the role of tumor microenvironment (TME) regulation by RT.
• To identify potential therapeutic strategies for enhancing the abscopal effect.

Main Methods:

• Established a dual tumor model (subcutaneous and lung metastases) in mice.
• Utilized single-cell RNA sequencing, immunofluorescence, and flow cytometry to analyze TME.
• Performed in vitro assays (luciferase reporter, RNA Pulldown, FISH) and in vivo studies.

Main Results:

• RT significantly suppressed tumor growth and lung metastasis, improving the TME.
• RT induced release of tumor exosomes containing circPIK3R3, which were internalized by macrophages.
• circPIK3R3 activated macrophages (M1 polarization) and promoted Type I Interferon (I-IFN) secretion via the miR-872-3p/IRF7 pathway.
• I-IFN activated the JAK/STAT pathway in CD8+ T cells, enhancing anti-tumor cytokine secretion (IFN-γ, GZMB).

Conclusions:

• Tumor-derived exosomes mediate the abscopal effect by transferring circPIK3R3 to macrophages.
• This process enhances anti-tumor immunity through macrophage polarization and subsequent CD8+ T cell activation.
• The circPIK3R3/miR-872-3p/IRF7 axis represents a novel pathway for modulating the immune response to RT.