Enhancing Immunotherapy in Lung Cancer: The Promise of dMMR/MSI-H Tumors and Immune Checkpoint Inhibitors

Lung cancer remains one of the most common causes of global cancer mortality, and approximately 85% of lung cancer diagnoses are classified as non-small cell lung cancer (NSCLC). Although surgery, chemotherapy, and radiotherapy have shown varying degrees of efficacy, the results may still not consistently lead to long-term improvements in cancer-specific survival rates. Immune checkpoint inhibitors (ICIs) have fundamentally altered cancer treatment paradigms owing to their unique mechanisms of action, which involve harnessing the immune system to target and destroy cancer cells. The PD-1/PD-L1 axis represents one of the pathways for which there are numerous immunotherapeutic options, and has shown particularly strong activity against tumors with a high mutational burden.

One factor that could enhance the responsiveness of tumors to these therapies is the presence of high microsatellite instability (MSI-H) or deficient DNA mismatch repair (dMMR), which could lead to an increased mutational burden of a tumor, making it more visible to the immune system. This study will discuss newly emerging strategies targeting dMMR/MSI-H in lung cancer using immune checkpoint inhibitors, the biology of dMMR/MSI-H, evidence to date, and future directions in this space.

Since only a minority of patients with NSCLC benefit from ICIs, it is essential and prudent to continue identifying prognostic markers, such as MSI-H/dMMR and other genomic or immune signatures.