Caloric restriction enhances radiosensitivity of colorectal tumors through the cGAS-STING pathway activation

Although radiotherapy is an important clinical option for colorectal cancer, its efficacy is limited by intrinsic tumor radioresistance and radiation-induced toxicity in surrounding normal tissues. This study investigated the radiosensitizing effects of either 7-day 30% caloric restriction (CR) or 24-hour fasting in a murine model bearing CT-26 colorectal tumor and explored the underlying mechanisms. CR and fasting pretreatment enhanced irradiation-induced tumor apoptosis, mitochondrial dysfunction, and cytosolic DNA stress, leading to activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS-STING) pathway, increased infiltration of tumor killing-associated CD8 + cytotoxic T lymphocytes, and modulation of macrophage polarization toward an antitumor phenotype. In addition, CR and fasting further suppressed the expression of glycolysis and lipid metabolism related proteins in the tumor microenvironment upon radiation exposure. By contrast, CR and fasting protected normal intestinal tissue from irradiation-induced damage. These findings were validated in vitro using CT-26 and normal small intestinal epithelial cells (IEC-6) cultured under medium with or without glucose. The critical role of the cGAS-STING pathway in enhancing radiosensitivity was confirmed through STING siRNA-mediated knockdown, combined with pharmacological intervention using the STING agonist MSA-2 and inhibitor H-151. In conclusion, our findings indicate that CR and fasting may increase the radiosensitivity of colorectal tumors, while reducing radiation injury to normal intestinal tissue.