A DNA repair defect that creates hypermutated, immunotherapy-responsive tumors.
The mismatch repair (MMR) system corrects DNA replication errors. When MMR genes (MLH1, MSH2, MSH6, PMS2) are inactivated–by mutation (Lynch syndrome) or epigenetic silencing–errors accumulate. Microsatellites are particularly vulnerable because their repetitive nature promotes polymerase slippage.
The resulting hypermutation generates abundant frameshift mutations and neoantigens, making MSI-H tumors highly immunogenic and responsive to checkpoint blockade.
What Goes Wrong: Microsatellite instability (MSI) occurs when DNA mismatch repair doesn't work. Short repetitive DNA sequences (microsatellites) accumulate errors, and mutations pile up throughout the genome.
The Result: High mutation rates create many abnormal proteins (neoantigens) that the immune system can recognize.
MSI-H/dMMR is the most successful predictive biomarker for immunotherapy. Response rates of 40-50% across tumor types led to FDA's first tissue-agnostic approval. However, MSI-H represents only ~4% of all solid tumors (higher in colorectal, endometrial).
Like TMBLoading..., MSI is an indirect biomarker–it identifies hypermutated tumors likely to be immunogenic but doesn't measure whether checkpoints are functionally engaged. Some MSI-H patients don't respond; some MSS patients do.
Strong Predictor: MSI-high tumors respond remarkably well to checkpoint inhibitors. Pembrolizumab is approved for MSI-high tumors regardless of cancer type.
Not Perfect: Not all MSI-high patients respond. And MSI status doesn't tell you about actual checkpoint engagement in the tumor.
MSI can be detected by PCR (microsatellite markers), IHC (MMR protein loss), or NGS. Testing is now standard in colorectal cancerLoading... and recommended in several other tumor types.
For MSS (microsatellite stable) tumors–the majority–other biomarkers are needed. This is where functional biomarkersLoading... measuring checkpoint engagement could fill the gap, identifying responders among the ~96% of patients who are MSI-stable.
What MSI Tells You: High mutation rate, many potential immune targets.
What It Doesn't Tell You: Whether checkpoints are actually engaged, whether T cells are present and active. Functional biomarkers could complement MSI testing.
