Reframing the paradigm: stereotactic body radiation therapy as an engineer of the tumor immune microenvironment

Stereotactic Body Radiation Therapy (SBRT) is undergoing a paradigm shift from a purely local ablative tool to a systemic immunomodulatory agent. However, a significant knowledge gap remains in understanding how to precisely "engineer" the tumor immune microenvironment (TME) to overcome resistance to immune checkpoint inhibitors (ICIs). Current approaches often rely on empirical combinations rather than biologically guided strategies.

We conducted a comprehensive narrative review of literature published up to January 2026 using PubMed and Web of Science databases. Keywords included "SBRT," "immunotherapy," "cGAS-STING," "abscopal effect," and "tumor microenvironment." We specifically synthesized evidence comparing the immunobiological impacts of ablative versus immunogenic doses (e.g., the TREX1-cGAS-STING axis) and analyzed organ-specific immune tolerance mechanisms.

Evidence suggests a "dose-dependent immunomodulatory window," where moderate hypofractionation (e.g., 8 Gy x 3) optimally induces type I interferons via the cGAS-STING pathway, whereas single high doses (>12-18 Gy) may dampen immunity through TREX1 induction. Beyond direct cytotoxicity, SBRT remodels the TME by depleting regulatory T cells and recruiting effectors, though this is often counterbalanced by a biphasic influx of MDSCs. Clinical translation faces challenges such as organ-specific immune tolerance, necessitating tailored triplet therapies.

Future success lies in a precision medicine approach: moving beyond generic combinations to "organ-specific triplets" (e.g., adding macrophage-targeting agents in liver disease) and implementing adaptive "closed-loop" protocols where real-time liquid biopsy feedback dictates the timing of the next SBRT pulse.