Biology and evolving management of resectable dMMR/MSI-H cancers: current status and future perspectives

Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors represent a biologically and immunologically distinct subset of solid malignancies. Defective DNA mismatch repair mechanisms in these tumors lead to the accumulation of insertion-deletion mutations, a hypermutated phenotype, and abundant tumor-specific neoantigens. These features drive robust T cell responses, explaining the remarkable sensitivity of dMMR/MSI-H tumors to immune checkpoint inhibitors (ICIs). Emerging evidence from clinical trials across resectable dMMR/MSI-H colorectal, gastric and gastroesophageal junction, and other solid tumors indicate that ICI therapy can induce profound pathological responses, including high rates of pathological complete response. These responses may permit organ preservation and reduce treatment-associated morbidity, offering a compelling alternative to conventional surgery-based approaches. Despite this promise, several challenges remain. Critical areas warranting further investigation include the refinement of patient selection strategies, clarification of the role of surgery in patients achieving a clinical complete response, and the identification of reliable predictive biomarkers for therapeutic response and resistance. In addition, the long-term oncologic outcomes associated with non-operative management remain to be elucidated. This review comprehensively summarizes the biological basis and emerging clinical evidence for immunotherapy in resectable dMMR/MSI-H solid tumors. We discuss current opportunities and ongoing challenges in refining curative-intent strategies, with the aim of improving outcomes and quality of life for patients with these immunologically distinct cancers.