Immune Checkpoint Inhibitors and Adverse Immunological Reactions

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple malignancies by blocking negative regulators of T-cell activation, most commonly cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By unleashing antitumour immunity, these agents can induce durable clinical responses, yet they also disrupt self-tolerance, giving rise to immune-related adverse events (irAEs). The spectrum of irAEs spans mild cutaneous eruptions to life-threatening myocarditis, encephalitis or severe endocrinopathies such as hypophysitis. Histologically, some reactions manifest as lymphohistiocytic infiltrates or non-caseating granulomas, mimicking sarcoidosis. Incidence varies by regimen and tumour type but can exceed 50% when combination therapy is employed. Early recognition relies on clinical vigilance, imaging and, where appropriate, tissue biopsy to distinguish irAEs from disease progression or infection. Management strategies include immunosuppressive tapering, corticosteroids and, in refractory cases, targeted biologics such as anti-TNF or anti-IL-6 antibodies. Ongoing efforts focus on predictive biomarkers, risk stratification and minimising long-term sequelae. As ICIs expand into adjuvant and non-oncological settings, understanding the mechanisms, diagnostic challenges and optimal management of adverse immunological reactions remains a global priority for patient safety and therapeutic innovation.

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Immune Checkpoint Inhibitors and Adverse Immunological Reactions publication trend

The graph below shows the total number of articles in immune checkpoint inhibitors and adverse immunological reactions across all publications each year (not limited to Nature Index journals).

Technical terms

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

Immune-related adverse events (irAEs): Inflammatory toxicities arising from off-target immune activation during checkpoint blockade, affecting various organs.

Sarcoidosis-like granulomatosis: Non-caseating granuloma formation in tissues, resembling sarcoidosis but triggered by immunotherapy.

Hypophysitis: Inflammation of the pituitary gland, often presenting with headache, hormonal deficiencies and imaging abnormalities.

Myocarditis: Inflammatory infiltration of the myocardium leading to arrhythmias, heart failure or sudden death.

Th17 cells: A subset of CD4+ T cells producing interleukin-17, implicated in autoimmune inflammation and irAE pathogenesis.

mTOR pathway: A central regulator of cell growth and metabolism; its dysregulation in immune cells can contribute to granulomatous inflammation.

References

1. Hilar/mediastinal and cutaneous drug-induced sarcoidosis-like reaction associated with immune checkpoint inhibitors in metastatic colorectal cancer: a case report. Frontiers in Immunology (2023).
2. Frequency and Consequences of Immune Checkpoint Inhibitor–Associated Inflammatory Changes in Different Organs: An Autopsy Study Over 13 -Years. Modern Pathology (2024).
3. Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients. Journal for ImmunoTherapy of Cancer (2018).