The New Horizon for Non-Metastatic dMMR Colorectal Cancer: A Systematic Review of the Adjuvant Chemoimmunotherapy and Neoadjuvant Immunotherapy Revolution

Background: The management of resected stage III colorectal cancer (CRC) has long been reliant on fluoropyrimidine-based adjuvant chemotherapy. However, the 10–15% of patients with mismatch repair-deficient (dMMR) tumors derive limited benefit from this approach. While immunotherapy has revolutionized the treatment of metastatic dMMR CRC, its role in the early-stage setting is rapidly evolving, creating a paradigm shift. Methods: A systematic literature review was conducted to identify pivotal clinical trials evaluating therapeutic strategies for non-metastatic dMMR CRC. Databases including PubMed/MEDLINE and conference proceedings from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) were searched up to June 2025. The review focused on phase II and III trials reporting on disease-free survival (DFS), pathological complete response (pCR), and safety. Study selection followed PRISMA guidelines. Results: The systematic review identified 14 key studies that were included for narrative synthesis. The evidence base encompassed three areas: (1) Foundational adjuvant chemotherapy trials (e.g., MOSAIC, IDEA); (2) Pivotal metastatic trials (e.g., KEYNOTE-177) validating immunotherapy efficacy in dMMR CRC; and (3) Modern trials in non-metastatic disease. The phase III ATOMIC trial demonstrated that adding atezolizumab to mFOLFOX significantly improved 3-year DFS versus chemotherapy alone (86.4% vs. 76.6%; Hazard Ratio [HR] 0.50, 95% Confidence Interval [CI] 0.34–0.72; p < 0.001). Concurrently, phase II neoadjuvant immunotherapy trials (e.g., NICHE-2) reported remarkable pCR rates of 68% and a 3-year DFS of 100%, with a more favorable safety profile compared to chemoimmunotherapy. Conclusions: The landscape for non-metastatic dMMR CRC is shifting from a chemotherapy-based model to an immunotherapy paradigm. The ATOMIC trial establishes adjuvant chemoimmunotherapy as a new standard, while robust neoadjuvant data suggest a potential future where short-course, chemotherapy-free immunotherapy could become a preferred strategy. Ongoing trials directly comparing these approaches are awaited.