Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block checkpoint molecules, which act as brakes on T cells, thereby enhancing the immune response against cancer cells1). While they have revolutionized cancer treatment, they also cause immune-related adverse events (irAEs) — nonspecific inflammation in tissues other than the tumor1).
The main target molecules and representative drugs are shown below1).
| Target Molecule | Representative Drug |
|---|---|
| CTLA-4 | Ipilimumab (Yervoy®), Tremelimumab |
| PD-1 | Nivolumab (Opdivo®), Pembrolizumab (Keytruda®), Cemiplimab |
| PD-L1 | Atezolizumab (Tecentriq®), Avelumab, Durvalumab |
CTLA-4 regulates T cell activation in lymph nodes, while PD-1 suppresses T cell responses in peripheral tissues1). Inhibition of these pathways promotes antitumor immunity but can also trigger autoimmune reactions. The Uveitis Clinical Practice Guidelines (2019) list ICIs as important causative agents of drug-induced uveitis3).
The incidence of ocular irAEs is 1–3%1). Posterior segment inflammation (retina/choroid) accounts for approximately 5–20% of all ocular irAEs, but it is more severe and can lead to permanent vision loss if not managed appropriately1). As the approved indications for ICIs expand, awareness in both ophthalmology and oncology becomes increasingly important.
Ocular irAEs occur overall at a frequency of 1–3%1). There are differences depending on the drug: approximately 1% with CTLA-4 monotherapy, 0.3–0.6% with PD-1 monotherapy, and a 2–3 times increased risk with combination therapy4). Most cases are dry eye or anterior uveitis, but posterior segment inflammation (5–20% of all ocular irAEs) can be a serious complication affecting visual prognosis.
Uveitis primarily presents with redness, blurred vision, photophobia, and eye pain. Posterior segment inflammation causes vision loss, floaters, and metamorphopsia1). Orbital myositis presents with diplopia, ptosis, and proptosis2). Dry eye mainly involves dryness and foreign body sensation.
ICI-related ocular irAEs can occur in almost all areas of the eye.
Anterior Segment/Ocular Surface
Dry eye (most frequent): PD-1/PD-L1 inhibitors can cause Sjögren’s syndrome-like decreased tear secretion.
Anterior uveitis: Anterior chamber inflammatory cells and flare. Accounts for 30–40% of all ocular irAEs. Many cases respond to steroid eye drops7).
Corneal erosion: May appear as part of Behçet-like syndrome.
Posterior Segment
VKH-like panuveitis: Exudative retinal detachment and optic disc edema. Occurs in 5–14% of melanoma ICI patients1). Mechanism involves cross-reactivity with melanin-containing cells.
Retinal vasculitis: Vascular leakage, macular edema, arteriovenous occlusion. Accounts for 5–10% of all ocular irAEs4).
Cystoid macular edema: Occurs with nivolumab, etc. Confirmed by OCT1).
Orbit
Orbital myositis (most common with anti-CTLA-4): Tends to occur bilaterally. MRI shows enlargement and contrast enhancement of extraocular muscles2).
Orbital fat inflammation: May extend to the orbital apex and superior orbital fissure2).
Thyroid eye disease-like inflammation: Can occur even in patients with normal thyroid function.
Neurologic
Ocular myasthenia gravis: Associated with anti-AChR antibody production. Reported with pembrolizumab9).
Optic neuritis: Early steroid treatment can preserve vision8).
Abducens nerve palsy: Often improves with drug discontinuation plus high-dose steroids8).
The onset of orbital inflammation ranges from 2 days to 2 months after the first dose2). In cases combined with systemic irAEs (myositis, myocarditis, colitis), caution is needed for severe progression.
The root cause of ocular irAEs from ICIs is the induction of autoimmune reactions due to the release of T-cell immune checkpoints1).
ICIs release T-cell immune checkpoints to attack cancer, but they also simultaneously disrupt the PD-L1-dependent immune privilege of ocular tissues1). The pathogenic mechanisms are classified into three types (see Section 6): (1) cross-reactivity between anti-tumor T cells and melanin-containing ocular tissues (VKH-like reaction), (2) retinal vasculitis due to bystander effects, and (3) autoantibody-mediated inflammation.
The diagnosis of ICI-related ocular irAEs is based on the temporal relationship between ICI use and ocular findings. Basic screening according to the Uveitis Clinical Practice Guidelines (2019) should be performed3). The principle of diagnosis is to confirm the temporal relationship between the suspected drug use and symptom onset, and to exclude other causes.
| Region | Main test | Purpose |
|---|---|---|
| Anterior segment | Slit-lamp microscopy | Anterior chamber inflammatory cells/flare, corneal findings |
| Posterior segment | OCT/FA | Loss of outer retinal layers, vascular leakage, cystoid macular edema1) |
| Posterior segment | Electroretinography (ERG) | Assessment of rod and cone function in MAR-like retinopathy |
| Orbit | MRI | Extraocular muscle enlargement/enhancement, orbital fat inflammation2) |
Anterior uveitis requires differentiation from infectious and non-infectious uveitis. VKH-like reactions are clinically similar to primary VKH, but a history of ICI use for melanoma is an important clue 1, 10). Orbital myositis requires differentiation from thyroid eye disease, IgG4-related disease, and idiopathic orbital inflammation 2). MAR (melanoma-associated retinopathy)-like retinopathy must be distinguished from paraneoplastic syndromes 1). Infectious uveitis and metastatic intraocular tumors (masquerade syndromes) should also be excluded.
Treatment is individualized according to CTCAE Grade in consultation between the oncologist and ophthalmologist. Discontinuation of the suspected drug is the principle of treatment, but because the antitumor effect of ICI is life-saving, the decision to discontinue should be made carefully by a multidisciplinary team.
| Grade | Severity | Ophthalmic Management | ICI Continuation |
|---|---|---|---|
| 1 | Mild (asymptomatic, slit-lamp findings only) | Topical steroids: Rinderon® 0.1% 4–6 times daily | Can continue |
| 2 | Moderate (1-step vision loss, anterior chamber inflammation) | Sub-Tenon injection: triamcinolone 20 mg + intensified steroid eye drops | Continue with caution |
| 3 | Severe (≥2-step vision loss, panuveitis) | Systemic PSL 1–2 mg/kg/day, tapered (after ocular symptom improvement) | ICI interruption |
| 4 | Risk of blindness | Steroid pulse: Solu-Medrol® 1 g/day × 3 days + immunosuppressant | Interruption; resumption difficult |
Anterior uveitis (Grade 1–2)
Moderate to severe posterior segment inflammation
Special conditions
Discontinuation of ICI is rarely necessary. For Grade 1–2, management with steroid eye drops and local injections while continuing ICI is often possible. For Grade 3 or higher (vision loss of 2 lines or more, panuveitis), systemic steroids and ICI interruption are recommended 5). For Grade 4 with risk of blindness, resumption may be difficult. Decisions to discontinue or resume must always be made in consultation with the oncologist.
After inflammation is adequately controlled (Grade 1 or lower), resumption may be considered in consultation with the oncologist. However, severe ocular irAE such as VKH-like panuveitis carry a high risk of recurrence, and the appropriateness of resumption should be determined on a case-by-case basis. After resumption, close ophthalmologic follow-up is necessary 6).
The eye is an immune-privileged organ, and the following mechanisms suppress T cell-mediated inflammation 1).
ICI directly targets these PD-1/PD-L1-dependent immune privilege mechanisms, creating a risk of intraocular T cell activation 1).
Haliyur et al. (2025) classified ICI-induced posterior segment irAE into three types 1).
Type 1: T Cell Cross-Reactivity
Type 1a: Anti-tumor T cells cross-react with ocular tissues such as melanin-containing cells, triggering VKH-like panuveitis. It occurs in 5–14% of melanoma patients 1).
Type 1b: Ocular-specific tissue-resident memory T cells are expanded and activated by ICIs, causing autoimmune retinopathy1).
Type 2: Bystander vasculitis
Systemic inflammation associated with ICI use nonspecifically disrupts the blood-retinal barrier1).
Perivascular lymphoplasmacytic infiltration by CD4+ T cells and upregulation of adhesion molecules cause retinal vasculitis and arteriovenous occlusion1).
Type 3: Autoantibody-mediated
PD-1 is also expressed on B cells, and ICIs induce expansion of B cell lineages and production of tissue-specific autoantibodies from plasma cells1).
It is also involved in exacerbation of paraneoplastic syndromes (such as MAR-like retinopathy)1).
Clinical findings are not limited to a single mechanism; multiple mechanisms may overlap. VKH-like panuveitis (Type 1a) presents with exudative retinal detachment and choroidal hyperfluorescence, and may be clinically indistinguishable from Harada disease1).
Anti-CTLA-4 inhibitors (ipilimumab) most frequently cause orbital inflammation2). Similar clinical features have been reported with anti-PD-1/PD-L1 inhibitors2). MRI shows enlargement and contrast enhancement of extraocular muscles and inflammatory changes in orbital fat, with a tendency for bilateral involvement2).
With the rapid expansion of ICI indications, the number of cases of ICI-related ocular irAE is expected to increase in the coming decades1).
Currently, understanding of the pathophysiology of posterior segment irAE is mainly based on case reports and case series, and diagnostic criteria and treatment guidelines have not been established1). Establishment of collaboration protocols between oncology and ophthalmology departments is urgently needed.
