Fungal intratumoral dysbiosis promoting PD-L1 expression in metastatic uveal melanoma with ocular inflammatory mimicry

Dear Editor, Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, accounting for approximately 3–5% of all melanomas worldwide. Pathophysiologically, UM arises from malignant transformation of uveal melanocytes, driven by mutations in GNAQ, GNA11, and BAP1, leading to dysregulated MAPK and PI3K signaling, genomic instability, and impaired DNA damage response[1]. Clinically, patients present with blurred vision, photopsia, or ocular pain, and advanced disease manifests with hepatic metastases. Despite enucleation, radiotherapy, and systemic chemotherapy, prognosis remains poor, with median survival under 15 months in metastatic cases[2]. Immunotherapy with PD-1/PD-L1 inhibitors has shown limited efficacy, underscoring the need to explore novel resistance mechanisms such as intratumoral microbial dysbiosis. Fungal intratumoral dysbiosis refers to the imbalance of commensal and pathogenic fungi within the tumor microenvironment. Mechanistically, fungal antigens activate pattern recognition receptors, inducing pro-inflammatory cytokines and upregulating PD-L1 on tumor and immune cells[3]. This promotes immune checkpoint activation, dampening cytotoxic T-cell responses. Diagnostic tools include metagenomic sequencing and immunohistochemistry to detect fungal signatures and PD-L1 expression. Therapeutically, antifungal modulation combined with checkpoint blockade has been proposed. Similar microbiome-driven PD-L1 regulation has been observed in colorectal cancer, pancreatic adenocarcinoma, non-small cell lung cancer, and hepatocellular carcinoma, where microbial dysbiosis worsens prognosis and reduces immunotherapy efficacy[4]. Recent studies illustrate translational relevance. In one investigation, Routy et al, demonstrated that fungal dysbiosis in pancreatic cancer promoted PD-L1 expression, reducing response to checkpoint inhibitors[4]. In parallel, Song et al, reviewed immunotherapy in UM, highlighting poor outcomes with PD-1/PD-L1 blockade and suggesting that microbial modulation may enhance efficacy[1]. Together, these findings underscore complementary strengths: fungal dysbiosis studies in systemic cancers validate the mechanism of PD-L1 induction, while UM immunotherapy literature highlights the urgent need for adjunctive strategies to overcome resistance. Despite promise, several hurdles limit clinical adoption. Microbiome profiling requires advanced sequencing platforms, which remain costly and inaccessible in resource-limited settings[5]. Establishing causality between fungal dysbiosis and PD-L1 expression is challenging due to tumor heterogeneity and confounding immune pathways. Antifungal therapies risk disrupting beneficial commensals, potentially worsening inflammation. Ethical concerns regarding invasive ocular sampling and regulatory barriers further constrain translation. Moreover, most evidence remains preclinical or observational, with limited validation in UM patient cohorts[6,7]. In conclusion, fungal intratumoral dysbiosis represents a novel mechanism of PD-L1 upregulation in metastatic UM, contributing to immune evasion and ocular inflammatory mimicry. Future strategies should prioritize multicenter validation using patient-derived xenografts, integration of microbiome profiling with transcriptomic and proteomic data, and exploration of antifungal-immunotherapy combinations. Cost-effectiveness analyses and awareness campaigns will be essential to facilitate adoption in resource-limited regions. Clinical drives to evaluate efficacy and side effects will be critical to establish trust and optimize outcomes. By advancing microbiome-targeted interventions, ophthalmic oncology may move closer to precision immunotherapy that improves survival in metastatic UM. This report adheres to the Transparency in the Reporting of Artificial Intelligence (TITAN) guidelines 2025[8].