Immune escape in colorectal cancer: Mechanisms and challenges of immune checkpoint inhibitor resistance

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally, with limited therapeutic success in its advanced stages. Immune checkpoint inhibitors (ICIs) are among the most significant immunotherapies in cancer treatment, revolutionizing the field. However, their effectiveness in CRC, particularly in microsatellite-stable (MSS) or proficient mismatch repair (pMMR) tumors, remains modest. This review examines the current landscape of ICI therapy in metastatic CRC, emphasizing FDA-approved agents that target PD-1, PD-L1, and CTLA-4, as well as emerging checkpoints like LAG-3 and TIM-3. In this study, we discuss key mechanisms underlying resistance to ICIs, which include factors from the tumor suppressor microenvironment, such as suppressor cells and cytokines, mechanisms of inhibiting or preventing the infiltration of effector lymphocytes, alongside tumor-intrinsic factors like defective antigen presentation, low tumor mutational burden, and activation of oncogenic pathways. Understanding these resistance mechanisms is crucial for developing effective combination strategies and improving patient outcomes. Advances in molecular profiling and immune modulation present promising opportunities to broaden the application of ICIs in the treatment of CRC.

Keywords: CTLA-4; Colorectal cancer; Immune checkpoint inhibitors; Immunotherapy; PD-1; Resistance mechanisms.