Mazandaran Association of Emergency Medicine Translational Health Reports 3092-6750 2 1 2025 12 20 Enhancing Anti-PD-1 Antibody Treatment in Colorectal Cancer: The Contribution of Innovative Immune Boosters and Inhibiting the USP2-PD-L1 Pathway 236684 10.22034/thr.2025.236684 EN Sarhang Hasan Azeez Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region,Iraq. 0000-0002-1327-0136 Journal Article Background: Colorectal cancer (CRC) remains a major global health issue, with advanced stages difficult to treat. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have improved cancer care, but they work well only in a small group of CRC patients with high microsatellite instability (MSI-H). Most CRC cases are microsatellite stable (MSS) and do not respond to ICI treatment alone, highlighting the need for combined therapies. Methods: This review summarizes recent studies from PubMed, Google Scholar, and clinical trial databases up to 2025 focusing on why CRC resists ICI treatment. It examines ways to modify the immunosuppressive tumor microenvironment (TME), including using immune-boosting agents and targeting proteins like USP2 that regulate PD-L1. Results: The immunosuppressive TME in MSS-CRC limits the effectiveness of PD-1 blockers. Immune adjuvants, such as the peptide NCL-P2, can reshape the TME by activating immune cells, increasing T cell entry into tumors, and reducing T cell exhaustion. Additionally, recent studies show that USP2 helps stabilize PD-L1 in cancer cells. Blocking USP2 leads to PD-L1 breakdown, improving T cell attack and boosting anti-PD-1 therapy in lab studies. Conclusion: Combining anti-PD-1 antibodies with treatments that alter the immunosuppressive TME—such as immune adjuvants to strengthen immune responses and USP2 inhibitors to lower PD-L1 levels—offers a promising multi-target strategy. This method could help overcome treatment resistance and extend immunotherapy benefits to more CRC patients.

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