Checkpoint Inhibitors and Combination Strategies in Colorectal Cancer: an Overview

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, intensifying the urgency for innovative therapeutic strategies. Current treatment paradigms primarily rely on cytotoxic chemotherapy; however, their efficacy is often compromised by systemic toxicity, resistance, and limited response rates—particularly in metastatic settings. Recent advancements in targeted therapies and immunotherapy, particularly immune checkpoint inhibitors (ICIs), offer promising alternative approaches, specifically for microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC. ICIs, such as anti-PD-1 and anti-CTLA-4 monoclonal antibodies, have demonstrated significant clinical benefits, particularly in the context of MSI-H/dMMR CRC, achieving improved ORRs and progression-free survival compared to traditional therapies. Despite these advancements, approximately 95% of CRC cases remain microsatellite stable (MSS) or low MSI (MSI-L), where ICIs have shown limited effectiveness. The complex tumor microenvironment and mechanisms driving immune evasion in MSS CRC underscore the need for further research into combination therapies targeting multiple immune checkpoints, such as LAG-3 and TIM-3, that may enhance antitumor responses in these patients. Moreover, ongoing clinical trials are exploring the role of novel immunotherapeutic strategies to broaden the applicability of ICIs in CRC treatment, aiming to identify biomarkers predictive of response and resistance. This review presents a comprehensive overview of the current landscape of CRC immunotherapy, emphasizing the critical distinction between MSI-H and MSS tumors and the robust potential of innovative combination therapies to improve outcomes for a broader spectrum of CRC patients, while addressing the persistent challenges in managing this heterogeneous disease