C5aR1 and cGAS/STING and their possible involvement in radiosensitivity of colorectal cancer

Worldwide, colorectal cancer (CRC) stands as the third leading cancer in terms of both diagnosis and mortality, underscoring its significant global health impact. Enhancing radiotherapy with radiosensitizers, such as C5aR1 (complement C5a receptor 1) blockade, has shown promise in treating resistant CRC, particularly in immunologically cold tumors. However, the molecular mechanisms by which C5aR1 inhibition improves radiosensitivity remain to be clarified. Reduced cGAS/STING (cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes) pathway activity is linked to radioresistance, while radiotherapy-induced cGAS/STING activation increases IFNB1 (interferon beta 1) and impairs DNA repair. Conversely, the complement component 5a (C5a)/C5aR1 axis suppresses STING-driven IFNB1 expression in immune responses, suggesting their distinct regulatory effects on cancer cell radiotherapy responses. Targeting C5aR1 may therefore enhance radiosensitivity by modulating the cGAS/STING pathway. This review examines potential interactions between C5aR1 and the cGAS/STING pathway, highlighting their relevance to addressing resistance mechanisms in CRC.