Samantha Mathew

Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States¹. The median 5-year survival for metastatic CRC is only 12.5%, and 25% of CRC is diagnosed at the metastatic stage, demonstrating a need to improve its treatment². Cells around the tumor in the tumor microenvironment (TME) impact tumor progression via immune response and inflammation. The cGAS-STING pathway is part of the innate immune system and responds to damaged double stranded DNA (dsDNA) in the cytosol. Downstream effects of this pathway include autophagy, cellular senescence, cell death, and enhanced adaptive immune response³. Since radiation damages DNA through ionization and reactive oxygen species production, its effect on cGAS-STING is being explored³.

Objectives: This review aims to understand the effects of cGAS-STING, how radiation affects it, and its impact on the TME and CRC suppression.

Methods: A search was conducted on the PubMed database from 2019-2024 with keywords “colorectal cancer,” “cGAS-STING pathway,” “immunotherapy,” “radiation therapy.”

Results: In mouse models, wild-type mice compared to STING-deficient knockout mice showed increased macrophage STING-mediated IL-18 and IL-1β expression. This induced the 4-1BBL/4-1BB pathway in macrophages to activate natural killer cells, demonstrating cGAS-STING’s impact on the TME⁴. Alternative delivery of traditional radiotherapy enhances cGAS-STING activation. Hafnium oxide electron dense nanoparticles activated by radiotherapy resulted in higher rates of CRC cell death, dsDNA breakage, micronuclei formation, and cGAS-STING activation⁵. Delivery of irinotecan encapsulated in a silica core with a lipid bilayer increased endocytosis efficacy by CRC cells. This combined with radiotherapy significantly increased cGAS-STING activation; increased proportions of CD4, CD8, and dendritic cells; and increased IFN-γ compared to either therapy alone, demonstrating synergy between therapies⁶. Heat-inactivated attenuated salmonella radiolabeled with iodine radionuclides was intratumorally injected into mouse CRC, demonstrating increased cGAMP, IFN-β, IL-2, and TNF-α levels⁷. Tumor samples of 32 rectal cancer patients were analyzed before and after radiotherapy. Increased expression of cGAS, ATF3, PTGS2, and IFN-β and increased CD8 cell density were observed following radiotherapy, signifying increased ferroptosis. Survival analysis found that high levels of these markers correlated with a significantly high disease-free survival rate⁸.

Conclusion: Activity of cGAS-STING can be modulated by radiotherapy, and its activation is related to better CRC prognosis. Efficient delivery methods may allow a lower therapeutic dose and fewer negative effects. However, cGAS-STING effects are multifaceted, and its other effects should be researched further. More broadly, TME knowledge could promote both new treatment and diagnosis methods.

Works Cited:

1. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal Cancer. The Lancet. 2019;394(10207):1467-1480. doi:https://doi.org/10.1016/s0140-6736(19)32319-0
2. Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nature Reviews Gastroenterology & Hepatology. 2019;16(6):361-375. doi:https://doi.org/10.1038/s41575-019-0126-x
3. Guo S, Yao Y, Tan Y, et al. Radiation-induced tumor immune microenvironments and potential targets for combination therapy. Signal Transduction and Targeted Therapy. 2023;8(1). doi:https://doi.org/10.1038/s41392-023-01462-z
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