Ocular Immune Toxicity in Cancer Immunotherapy, From Immune Privilege Breakdown to Treatment Rechallenge: A Review.

Abstract

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but can disrupt ocular immune privilege and produce heterogeneous immune-related adverse events (Eye-irAEs). This structured narrative review with evidence mapping integrates clinical, epidemiologic, mechanistic, pharmacovigilance, and management data to define translational pathways from checkpoint blockade to ocular toxicity and treatment decisions. In a real-world cohort of 41,020 ICI-treated patients, ophthalmic irAEs occurred in 4.18% within 1 year, including dry eye disease in 2.00%, conjunctivitis in 0.87%, blepharitis in 0.51%, anterior uveitis in 0.39%, and keratitis in 0.38%. A 2026 meta-analysis of five cohorts comprising 277,790 participants found increased uveitis risk with ICI exposure (hazard ratio 2.26), while pooled overall survival was not significantly associated with ICI-related uveitis (hazard ratio 0.69, 95% CI 0.35-1.39). Among patients with preexisting uveitis, recurrence reached 38.9% for prior anterior disease and 51.1% for prior intermediate, posterior, or panuveitis. Risk varies by malignancy and regimen; melanoma was associated with substantially greater noninfectious uveitis than lung cancer (1.10% vs 0.18%; risk ratio 6.17, 95% CI 4.20-9.08). Mechanistically, PD-1/PD-L1 and CTLA-4 have the strongest established exposure-toxicity evidence, LAG-3 signals are emerging, and TIM-3 and TIGIT remain translational. Phenotype-directed local or systemic therapy can preserve vision and permit ICI continuation or rechallenge in selected patients. In a 2026 rechallenge series, four of five rechallenged patients had no documented recurrence, while one recurrence resolved successfully with corticosteroid treatment. Standardized phenotyping, longitudinal ophthalmic surveillance, multidisciplinary attribution, and prospective ocular endpoints should translate mechanistic insight into safer immunotherapy, individualized rechallenge, and improved cancer-treatment continuity.