Synergistic Mechanisms of Radiotherapy and Immune Checkpoint Blockade in Restoring the Ecological Balance of the Tumor Microenvironment

Duke Kunshan University, Undergraduate Department, 215316, Suzhou, Jiangsu Province, China

^* Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.

Abstract

The therapeutic efficacy of immune checkpoint blockade (ICB) in Non-Small Cell Lung Cancer (NSCLC) is fundamentally constrained by the “immune-excluded” (cold) phenotype. This ecological state is characterized by a potent ‘biological wall’—comprising a dense extracellular matrix and suppressive myeloid niches—which physically and metabolically excludes functional CD8+ T cells from the tumor core. This study demonstrates that radiotherapy (RT) functions as a strategic biophysical primer to dismantle these barriers. By triggering the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway through the sensing of cytosolic double-stranded DNA (dsDNA), RT initiates a molecular cascade that drives Type I interferon production, the repolarization of M2 macrophages to an M1 phenotype, and the depletion of myeloid-derived suppressor cells (MDSCs). Furthermore, the dose-dependent “sweet spot” necessary to avoid three-prime repair exonuclease 1 (TREX1)-mediated immune silencing is discussed. By establishing favorable chemokine gradients, RT transforms a suppressive ecosystem into an “inflamed” niche, enhancing ICB sensitivity. This review provides a roadmap for integrating RT and ICB, highlighting the potential of artificial intelligence (AI) driven precision protocols to achieve sustainable ecological homeostasis in oncology.