Immune Checkpoint Inhibition in Colorectal Cancer

Immune checkpoint inhibition has transformed the therapeutic landscape of colorectal cancer by releasing intrinsic brakes on cytotoxic T-cell activity. Antibodies targeting programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) disrupt inhibitory signals within the tumour microenvironment, facilitating sustained antitumour immunity. Clinical benefit has been most pronounced in tumours with deficient mismatch repair or high levels of microsatellite instability (dMMR/MSI-H), which harbour abundant neoantigens and evoke robust lymphocytic infiltration. In this subset, agents such as pembrolizumab, nivolumab and combinations with ipilimumab yield durable responses and have obtained regulatory approval in first-line and refractory settings. Nonetheless, the majority of colorectal cancers are proficient in mismatch repair and demonstrate limited single-agent activity, prompting development of combination regimens that integrate checkpoint blockade with chemotherapy, radiotherapy or targeted agents. Mechanistic insights implicate factors such as tumour mutational burden, neoantigen clonality, interferon-γ pathway integrity, antigen-presenting macrophage interactions and spatial organisation of T cells as determinants of response. Neoadjuvant immunotherapy trials in locally advanced disease report high rates of pathological response, suggesting potential for organ preservation in selected patients. Advances in circulating tumour DNA monitoring, composite biomarker panels and adaptive trial designs aim to expand efficacy, overcome primary and acquired resistance, and deliver personalised checkpoint-based therapies to a broader colorectal cancer population.

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Immune Checkpoint Inhibition in Colorectal Cancer publication trend

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

Technical terms

Immune checkpoint inhibitors: Monoclonal antibodies that block inhibitory receptors or ligands to enhance T-cell-mediated tumour killing.

dMMR/MSI-H: Tumours with deficient DNA mismatch repair leading to high microsatellite instability and increased neoantigen burden.

Tumour mutational burden (TMB): The total number of somatic mutations per coding area of a tumour genome, correlating with neoantigen load.

Neoadjuvant immunotherapy: Checkpoint blockade administered prior to surgical resection to elicit tumour regression.

Pseudoprogression: Apparent tumour enlargement on imaging due to immune cell infiltration rather than true tumour growth.

References

1. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability. Annals of Oncology (2023).
2. Transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors to identify determinants of responsiveness to anti-PD-1 therapyTranscriptomic Profile of MSI-H/dMMR Gastrointestinal tumors. Clinical Cancer Research (2022).
3. Efficacy and Safety of Neoadjuvant Monoimmunotherapy With PD-1 Inhibitor for dMMR/MSI⁃H Locally Advanced Colorectal Cancer: A Single-Center Real-World Study. Frontiers in Immunology (2022).
4. Circulating tumor DNA (ctDNA) serial analysis during progression on PD-1 blockade and later CTLA-4 rescue in patients with mismatch repair deficient metastatic colorectal cancer. Journal for ImmunoTherapy of Cancer (2022).
5. Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency. Cancers (2021).
6. Predictive biomarkers of colon cancer immunotherapy: Present and future. Frontiers in Immunology (2022).