Purpose: Colorectal cancer (CRC) is a highly prevalent malignant tumor worldwide, and the emergence of immune checkpoint inhibitors (ICIs) has changed CRC immunotherapy. This systematic review aims to provide a comprehensive overview of registered clinical trials on ICIs in CRC worldwide, with a focus on major molecular targets, combination therapy strategies, geographic distribution patterns, and future directions for precision immunotherapy.
Methods: All clinical trials related to ICIs in CRC were retrieved. Trials were screened according to inclusion and exclusion criteria, and core information such as trial phase, conducting country, mechanism targets, and combination therapy, was systematically organized for retrospective and trend analyses.
Results: A total of 1,479 eligible clinical trials were included. There has been a steady increase in the number of registered trials, with Phase II trials being the most numerous. The United States and China lead globally in the number of trials reported. Key research targets included PD-1, PD-L1, CTLA-4, and molecules related to the tumor microenvironment. Combination therapies involving ICIs, anti-angiogenic agents, and targeted drugs across multiple pathways emerged as a new research focus.
Conclusion: ICIs have driven the development of precision immunotherapy for CRC, and multi-target combination therapies hold promise for improving outcomes. However, clinical translation and efficacy improvements remain challenging. Future studies should focus on the mechanisms involved and accumulating clinical data to guide more effective immunotherapy strategies.
Keywords: clinical trials; colorectal cancer; combination therapy; immune checkpoint inhibitors; tumor microenvironment.
© 2025 Li et al.