Ocular Complications of Cancer Immunotherapy: Mechanisms, Clinical Features, and Management

Nada Ali

Introduction

Immunotherapy has revolutionised cancer treatment by providing significant survival advantages across a variety of cancers. It works by leveraging the body’s immune system to detect and destroy cancer cells, marking a considerable departure from traditional cytotoxic therapies (1). Nonetheless, boosting immune activity can also disrupt immune tolerance, leading to immune-related adverse events (irAEs) that may affect multiple organs, including the eyes (2). Although ocular irAEs linked to immune checkpoint inhibitors are relatively rare, occurring in about 2.8–3.6% of patients treated, with dry eye and uveitis being the most common, they emphasise the need for awareness and understanding as these treatments become more widespread (3-5). This review aims to explain the mechanisms of immunotherapy-induced immune dysregulation, describe common and serious ocular side effects, and emphasise the importance of prompt diagnosis and management.

Pathophysiology

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory immune receptors, most commonly cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) (6). By blocking these pathways, ICIs enhance tumour-specific T-cell–mediated immune responses and have therefore become integral to the treatment of a wide range of malignancies (7). Under physiological conditions, immune checkpoint molecules play a critical role in maintaining immune homeostasis and preventing autoimmunity; however, many cancers exploit these pathways to evade antitumour immune surveillance (6,7).

Despite their clinical efficacy, ICIs are associated with a significant risk of autoimmune toxicity, reflecting the loss of self-tolerance required to achieve effective antitumour immunity (8). Immune-related adverse events (irAEs) arise from this fundamental mechanism of immune disinhibition, whereby enhanced T-cell activation augments antitumour responses while simultaneously disrupting peripheral tolerance (9). In the eye, this process can give rise to a broad spectrum of autoimmune-like inflammatory conditions, ranging from mild ocular surface disease to severe, vision-threatening pathology (10). Interference with key regulatory pathways, such as CTLA-4 and PD-1/PD-L1, permits the expansion of autoreactive T cells that may target healthy ocular tissues (2). The underlying pathophysiology is thought to involve both direct inflammatory infiltration and secondary bystander damage, often presenting as granulomatous inflammation or lacrimal gland dysfunction (2). Furthermore, immune checkpoint blockade may unmask ocular self-antigens, triggering an autoimmune cascade in a systemic pro-inflammatory environment induced by ICIs (4, 9, 11).

Clinical presentation

The clinical manifestations of immunotherapy-induced ocular adverse events are highly heterogeneous, ranging from mild ocular discomfort to severe, vision-threatening disease. Commonly reported ocular irAEs include uveitis and dry eye disease (12). Additional anterior segment findings include conjunctivitis, typically presenting with ocular redness, irritation, and foreign-body sensation, as well as more severe complications such as corneal perforation (12-13). Less frequent but potentially sight-threatening manifestations include central serous retinopathy–like reactions, panuveitis, and optic neuropathy, all of which require prompt recognition and intervention to prevent irreversible visual loss (12-13).

Neuro-ophthalmic complications, while relatively uncommon, are clinically significant and may present as cranial neuropathies with ophthalmoplegia or, more rarely, giant cell arteritis–like syndromes associated with acute and profound vision loss (14). Retinal involvement has also been described, including retinopathy and choroidopathy, often manifesting as visual field defects or metamorphopsia secondary to subretinal fluid accumulation (15).

Extraocular muscle dysfunction, including ophthalmoplegia and ptosis, is also observed, with ptosis often representing an early clinical sign (12). Additional reported ocular toxicities include punctate epithelial erosions, subconjunctival haemorrhage, hypotony maculopathy, cystoid macular oedema, serous retinal detachment, choroiditis, Vogt–Koyanagi–Harada–like syndrome, and melanoma-associated retinopathy (16). Rare neuro-ophthalmic entities such as optic neuritis, neuroretinitis, oculomotor nerve palsy, bilateral internuclear ophthalmoplegia, and opsoclonus–myoclonus–ataxia syndrome have also been reported, with many cases demonstrating improvement following corticosteroid therapy (14).

Ocular irAEs typically develop within a median of approximately two months following initiation of immunotherapy and may occur concurrently with systemic immune-related adverse events, necessitating heightened clinical vigilance for multisystem involvement (17). Consequently, any patient receiving immunotherapy who presents with new visual symptoms should undergo a comprehensive ophthalmic evaluation, as early diagnosis is critical to optimizing visual outcomes.

Management

Management of ocular immune-related adverse events is personalised and requires close collaboration between ophthalmologists and oncologists. Given the relatively low incidence of ocular irAEs, long-term outcomes and prognosis remain incompletely understood (13-14). Most ocular toxicities can be effectively managed or resolved using topical or systemic corticosteroid therapy (5). In the absence of ophthalmology-specific protocols, management is usually guided by severity-based consensus guidelines (18-19). Low-grade ocular toxicities generally do not require corticosteroid therapy or discontinuation of immune checkpoint inhibitor treatment. In contrast, higher-grade adverse events may require temporary or permanent cessation of immunotherapy and the initiation of systemic corticosteroid therapy (18-19).

Conclusions

As the clinical use of immune checkpoint inhibitors continues to expand, ocular immune-related adverse events are increasingly being recognised. A clear understanding of their underlying immunopathology, wide-ranging clinical presentations, and severity-based management approaches is essential for both oncologists and ophthalmologists to prevent vision-threatening complications and improve patient outcomes.

References

  1. Winges KM, Gordon LK. Neuro-ophthalmic complications of immune checkpoint inhibitor therapy: current status and future directions. Front Ophthalmol. 2022;2:1044904. doi:10.3389/fopht.2022.1044904
  2. Masalkhi M, Wahoud N, Moran B, Elhassadi E. Impact of immune checkpoint inhibitors on vision and eye health. Eye (Lond). 2024;38(15):2854. doi:10.1038/s41433-024-03212-z
  3. Oskam JA, Danesh-Meyer HV. Neuro-ophthalmic complications of modern anti-cancer drugs. Graefes Arch Clin Exp Ophthalmol. 2024;262(7):2269. doi:10.1007/s00417-023-06350-4
  4. Sun MM, Levinson RD, Filipowicz A, Anesi SD, Kaplan HJ, Wang W, Goldstein DA, Gangaputra S, Swan RT, Sen HN, Gordon LK. Uveitis in patients treated with CTLA-4 and PD-1 checkpoint blockade inhibition. Ocul Immunol Inflamm. 2020;28(2):217–225. doi:10.1080/09273948.2019.1577978
  5. Fortes BH, Liou H, Dalvin LA. Ophthalmic adverse effects of immune checkpoint inhibitors: the Mayo Clinic experience. Br J Ophthalmol. 2021;105(9):1263–1271. doi:10.1136/bjophthalmol-2020-316970
  6. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805–812.
  7. Garrett MD, Collins I. Anticancer therapy with checkpoint inhibitors: what, where and when? Trends Pharmacol Sci. 2011;32(5):308–316. doi:10.1016/j.tips.2011.02.014
  8. Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019;5(7):1008–1019.
  9. Martens A, Schauwvlieghe P, Madoe A, Casteels I, Aspeslagh S. Ocular adverse events associated with immune checkpoint inhibitors: a scoping review. J Ophthalmic Inflamm Infect. 2023;13(1):21. doi:10.1186/s12348-022-00321-2
  10. Gan L, Chen H, Liu X, Zhang L. Ophthalmic immune-related adverse events associated with immune checkpoint inhibitors. Front Immunol. 2023;14:1130238. doi:10.3389/fimmu.2023.1130238
  11. Zhang H, Houadj L, Wu KY, Tran SD. Diagnosing and managing uveitis associated with immune checkpoint inhibitors: a review. Diagnostics (Basel). 2024;14(3):336. doi:10.3390/diagnostics14030336
  12. Zhou L, Wei X. Ocular immune-related adverse events associated with immune checkpoint inhibitors in lung cancer. Front Immunol. 2021;12:701951. doi:10.3389/fimmu.2021.701951
  13. Vishnevskia-Dai V, Rozner L, Berger R, Jaron Z, Elyashiv S, Markel G, et al. Ocular side effects of novel anti-cancer biological therapies. Sci Rep. 2021;11(1):787. doi:10.1038/s41598-020-80898-7
  14. Yu CW, Yau M, Mezey N, Joarder I, Micieli JA. Neuro-ophthalmic complications of immune checkpoint inhibitors: a systematic review. Eye Brain. 2020;12:139–167. doi:10.2147/EB.S277760
  15. Zhang H, Yuan AT, Chiasson N, Wu KY, Kalevar A. Immune checkpoint inhibitor-associated Vogt–Koyanagi–Harada-like syndrome: a descriptive systematic review. J Ophthalmic Inflamm Infect. 2025;15(1):12. doi:10.1186/s12348-025-00484-8
  16. Kim JM, Materin MA, Sznol M, Kluger HM, Weiss SA, Chow J, et al. Ophthalmic immune-related adverse events of immunotherapy: a single-site case series. Ophthalmology. 2019;126(7):1058–1065. doi:10.1016/j.ophtha.2019.01.031
  17. Connolly CM, Bambhania K, Naidoo J. Immune-related adverse events: a case-based approach. Front Oncol. 2019;9:530. doi:10.3389/fonc.2019.00530
  18. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO clinical practice guideline. J Clin Oncol. 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385
  19. Puzanov I, Diab A, Abdallah K, Bingham CO, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer. J Immunother Cancer. 2017;5(1):95. doi:10.1186/s40425-017-0300-z

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