Chronic and Emerging Immune-Related Adverse Events from Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by restoring antitumor immunity, but cause immune-related adverse events (irAEs), inflammatory toxicities from disrupted peripheral tolerance. As ICIs expand into adjuvant settings, irAEs critically impact quality of life and treatment continuity. Any-grade irAE incidence reaches 60–90%, with grade ≥ 3 toxicities in 10–20% (anti-PD-1/PD-L1 monotherapy), 31% (anti-CTLA-4), and 55% (combination therapy). Fatal irAEs remain rare (0.36–1.23%). Onset timing varies: CTLA-4 inhibitors typically manifest within 21 days versus 40 days for PD-1/PD-L1. Mechanistically, irAEs arise from checkpoint blockade disrupting inhibitory T-cell signals. Tissue-resident memory T-cells drive organ-specific manifestations through Th1/Tc1 polarization. Checkpoint expression patterns explain site-specific toxicity: CTLA-4 on pituitary regulatory T-cells predisposes to hypophysitis, while PD-L1 renal expression associates with nephritis. Endocrine irAEs predominate (10–40%), with hypothyroidism requiring lifelong replacement. Hypophysitis affects 1.9–14%, with 69–100% requiring permanent hormone supplementation. Gastrointestinal toxicities reach 50% with combination therapy, though 20–40% prove corticosteroid-refractory. Cardiovascular irAEs, though rare (<1%), carry highest mortality (myocarditis: 38%). Chronic irAEs persist in 40–50% of patients. Two phenotypes require divergent treatment: "burnout" irAEs from immune-mediated destruction (endocrinopathies with 83–100% chronicity) requiring hormone replacement, and "smoldering inflammation" (arthritis, myocarditis) responsive to anti-inflammatory therapy. Steroid-refractory cases benefit from IL-6 blockade (73% improvement) and JAK-STAT inhibition (96.7% remission). ICI rechallenge demonstrates 31.8% toxicity recurrence. The field lacks validated biomarkers distinguishing smoldering from burnout phenotypes, limiting precision management, a critical research priority.