Immune Checkpoint Inhibitor-Induced Gastrointestinal Adverse Events

Immune checkpoint inhibitors (ICIs) have transformed oncology by unleashing T cell–mediated antitumour responses through blockade of regulatory receptors such as CTLA-4 and PD-1. However, by disrupting physiological brakes on the immune system, ICIs can provoke immune-related adverse events (irAEs) in multiple organs, with the gastrointestinal tract among the most commonly affected. Clinical manifestations range from mild diarrhoea to fulminant colitis characterised by mucosal ulceration, bleeding and risk of perforation. Pathophysiologically, irAE colitis involves aberrant activation of effector lymphocytes, loss of regulatory T cell function and perturbation of the gut microbiota, leading to barrier disruption and local inflammation. Standard management relies on systemic corticosteroids, often supplemented by biological agents such as tumour necrosis factor–α inhibitors or gut-specific antibodies. Striking a balance between controlling life-threatening inflammation and preserving antitumour immunity remains a central challenge. Emerging insights into cytokine pathways, cellular drivers and endoscopic biomarkers promise to refine risk stratification and enable targeted therapies that mitigate gastrointestinal toxicity without compromising cancer control.

Research from Nature Portfolio

A preclinical study employing combination anti-CTLA-4 and anti-PD-1 therapy in murine models has delineated a pivotal role for the interleukin 23/interferon γ (IL23/IFNγ) axis in checkpoint inhibitor–induced colitis. Bulk and single-cell transcriptomic analyses revealed expansion of polyfunctional lymphocytes that co-produce IFNγ, granzyme B and chemokines, with disease severity modulated by the composition of the intestinal microbiota. Therapeutic blockade of IL23 or IFNγ markedly attenuated colonic inflammation and restored mucosal homeostasis, establishing cytokine neutralisation as a promising avenue for reversing immune-mediated intestinal injury.

Immune Checkpoint Inhibitor-Induced Gastrointestinal Adverse Events publication trend

The graph below shows the total number of articles in immune checkpoint inhibitor-induced gastrointestinal adverse events across all publications each year (not limited to Nature Index journals).

Technical terms

Immune checkpoint inhibitors (ICIs): Monoclonal antibodies that block inhibitory receptors on T cells (e.g., CTLA-4, PD-1) to enhance antitumour immunity.

Immune-related adverse events (irAEs): Off-target inflammatory toxicities arising from immune checkpoint blockade, affecting organs such as the colon.

Colitis: Inflammation of the colon presenting clinically with diarrhoea, abdominal pain and potential mucosal ulceration.

Tissue resident memory T cells (TRM cells): A non-circulating subset of T lymphocytes that persists within tissues and mediates local immune responses.

IL23/IFNγ axis: A proinflammatory cytokine cascade in which interleukin 23 promotes interferon γ production by effector lymphocytes, driving intestinal inflammation.

Anti-TNFα therapy: Biological agents that neutralise tumour necrosis factor-α to reduce immune-mediated tissue injury.

Integrin α4β7: A gut-homing receptor on lymphocytes targeted by vedolizumab to achieve intestinally restricted immunosuppression.

References

1. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nature Communications (2023).
2. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends in Molecular Medicine (2024).
3. Interferon-Gamma–Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor–Colitis. Gastroenterology (2021).
4. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open (2018).