Neoadjuvant Immune Checkpoint Inhibition in MSI-H/dMMR Colorectal Cancer: A Systematic Review of Prospective Trials Evaluating Efficacy, Pathologic Response, and Surgical Outcomes.

backgroundMismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) colorectal cancers demonstrate exceptional responsiveness to immune checkpoint inhibitors; however, evidence for the efficacy of neoadjuvant immunotherapy remains limited. This review consolidates all prospective trials evaluating neoadjuvant immune checkpoint blockade in non-metastatic dMMR/MSI-H colorectal cancer.

methodsThis systematic review followed the PRISMA guidelines and was registered with the PROSPERO database (CRD420251074066). A comprehensive search of PubMed, Embase, CENTRAL, and ClinicalTrials.gov was conducted until May 2025. Prospective interventional studies involving neoadjuvant immunotherapy in adults with stage II-III dMMR/MSI-H colorectal adenocarcinoma were included in this review. The primary outcomes were pathological complete response (pCR), major pathological response (MPR), and clinical complete response (cCR). The risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions tool.

resultsEight prospective phase 2 trials encompassing 352 patients with stage II-III dMMR/MSI-H colorectal cancer were included. The pCR rates ranged from 41 to 90%, with the highest responses in patients with colon cancer receiving dual checkpoint blockade (nivolumab plus ipilimumab: 90% pCR, 95% MPR). In rectal cancer, 100% of patients receiving dostarlimab (n = 16) and 46% of those in the camrelizumab plus apatinib group (n = 24/52) achieved cCR with organ preservation. MPR was observed in 80-95% of the studies. Grade ≥ 3 adverse events occurred in 3-34% of patients, with no treatment-related deaths reported. At the median follow-up (8-26 months), disease-free survival exceeded 98% in most cohorts. Watch-and-wait strategies are durable, with no local regrowth in patients with complete clinical response (cCR).

conclusionsNeoadjuvant immune checkpoint inhibition demonstrates high pathological and clinical response rates in dMMR/MSI-H colorectal cancer, with organ preservation achievable in selected rectal cancer patients. Neoadjuvant immunotherapy may become an alternative to surgery as the primary treatment for MSI-H/dMMR colorectal cancer if long-term quality of life is superior and toxicity and cost are competitive with standard surgical approaches. However, longer follow-up, predictive biomarkers, and randomized comparisons with upfront surgery are required before its routine clinical use.