Early- and advanced-stage MSI-H non-colorectal cancers: best management and challenges in 2025.

Gastrointestinal malignancies account for the vast majority of tumours within the microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) phenotype. Over the past decade, evidence on the prognostic and predictive role of MSI-H/dMMR status has steadily accumulated, and immune checkpoint inhibitors (ICIs) are now considered the cornerstone of treatment for all patients with advanced MSI-H/dMMR cancers. However, in non-colorectal tumours the available evidence is less robust, raising important challenges, such as defining the optimal therapeutic regimen across different treatment lines and establishing the appropriate duration of therapy. More recently, the efficacy of ICIs has also been demonstrated in localized disease, prompting new questions regarding their integration into curative-intent strategies, such as the risk of overtreatment given the favourable prognosis of early-stage tumours, the role of nonoperative management, the optimal treatment regimen, and schedule. In this review, we summarize the available literature and the evidence supporting treatment strategies for patients with early- and advanced-stage MSI-H/dMMR non-colorectal cancers.