Microsatellite instability (MSI) is one of the most important molecular characteristics of a tumor, which occurs among various tumor types. In this review article, we examine the molecular characteristics of MSI tumors, both sporadic and Lynch-associated. We also overview the risks of developing hereditary forms of cancer and potential mechanisms of tumor development in patients with Lynch syndrome. Additionally, we summarize the results of major clinical studies on the efficacy of immune checkpoint inhibitors for MSI tumors and discuss the predictive role of MSI in the context of chemotherapy and checkpoint inhibitors. Finally, we briefly discuss some of the underlying mechanisms causing therapy resistance in patients treated with immune checkpoint inhibitors.

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Accurate microsatellite instability (MSI) assessment is critical for Lynch syndrome diagnostics, prognosis of disease progression, and success of chemotherapy and immunotherapy. In immunotherapy, false-positive MSI testing prevents putative responding patients from receiving effective treatment, and false-negative MSI testing leads to the prescription of ineffective therapy with its adverse effects. Knowledge GeneratedThis article provides the main advantages and limitations of the standard MSI testing methods and novel approaches in clinical practice, assesses possible sources of errors, discusses best practices and guidelines, and highlights the unsolved questions that remain sources of incorrect interpretation. RelevanceAmong novel approaches, next-generation sequencing (NGS) is considered one of the most promising; its advantages include high accuracy, an expanded spectrum of microsatellites analyzed, and simultaneous assessment of a comprehensive spectrum of clinically significant markers. In liquid biopsy, NGS-based approaches demonstrate outstanding results.