Immune Mechanisms in Microsatellite Unstable Colorectal Cancer

Defective DNA mismatch repair leads to microsatellite instability (MSI), characterised by frequent insertion and deletion mutations within repetitive DNA regions. In colorectal tumours, high MSI produces a rich array of novel peptide sequences—neoantigens—that attract cytotoxic T lymphocytes into the tumour microenvironment. Activation of innate sensors such as the cGAS–STING pathway and type I interferon signalling further amplifies antitumour immunity. This heightened immunogenicity underlies the favourable prognosis of non-metastatic MSI-high colorectal cancer and its pronounced sensitivity to immune checkpoint inhibitors. However, sustained immune pressure drives immunoediting: clones bearing the most immunogenic frameshift peptides are eliminated, while those with reduced antigenicity or defects in antigen presentation—such as loss of HLA class I expression or β2-microglobulin mutations—emerge. Additional escape mechanisms include modulation of the tumour microenvironment through immunosuppressive cell populations, stromal barriers to T-cell infiltration and epigenetic silencing of immune genes. Understanding these dynamic interactions has informed strategies to broaden neoantigen targeting, enhance T-cell recruitment and overcome resistance, aiming to deliver durable clinical benefit to a wider spectrum of patients with MSI-unstable colorectal cancer.

Research from Nature Portfolio

Recent studies have characterised the shared frameshift mutation landscape across microsatellite-unstable colorectal tumours, providing direct evidence of immunoediting during tumour evolution. By quantifying insertion/deletion events at coding microsatellites and predicting neoantigen immunogenicity, researchers found a negative correlation between mutation frequency and peptide antigenicity, indicating selective elimination of highly immunogenic clones. Persisting outlier mutations, which generate functionally confirmed neoantigens, suggest driver roles and represent promising targets for development of preventive or therapeutic vaccines.

Immune Mechanisms in Microsatellite Unstable Colorectal Cancer publication trend

The graph below shows the total number of articles in immune mechanisms in microsatellite unstable colorectal cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Microsatellite instability (MSI): A hypermutable state caused by failure of DNA mismatch repair, leading to length variations in short repetitive sequences.

Neoantigen: A tumour-specific peptide arising from somatic mutations that is recognised as foreign by the immune system.

Immunoediting: The dynamic process by which immune surveillance shapes tumour antigenicity through phases of elimination, equilibrium and escape.

Tumour microenvironment (TME): The complex assembly of cancer cells, stromal elements and immune infiltrates that surrounds and interacts with a tumour.

Immune checkpoint inhibitor (ICI): A therapeutic antibody that blocks inhibitory receptors on T cells (e.g., PD-1, CTLA-4) to enhance antitumour immune responses.

cGAS–STING pathway: An innate immune sensing mechanism activated by cytosolic DNA, driving type I interferon production and inflammatory responses.

References

1. Single-cell spatial immune profiling for precision immunotherapy in Lynch syndrome. Journal of the National Cancer Center (2024).
2. Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome. Journal of the National Cancer Institute (2024).
3. The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution. Nature Communications (2020).