REVIEW article
Front. Cell Dev. Biol.
Sec. Cancer Cell Biology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1619150
This article is part of the Research TopicAdvancements in Solid Tumor Immunotherapy: Enhancing Efficacy and Overcoming ResistanceView all articles
Advances in Immunotherapy for Uveal Melanoma: Enhancing Efficacy and Overcoming Resistance
Provisionally accepted
- 1Department of Ophthalmology, Shanghai Changzheng Hospital, Huangpu, China
- 2Department of Ophthalmology, No.906 Hospital of People's Liberation Army, Ningbo, China
- 3Department of Anesthesiology, Shanghai Changzheng Hospital, Huangpu, China
- 4Department of Ophthalmology, People's Liberation Army Navy 971 Hospital, Qingdao, Shandong Province, China
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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, presenting a significant clinical challenge due to its high metastatic potential and limited response to conventional systemic therapies. While immunotherapy has transformed the treatment landscape for numerous cancers, its effectiveness in UM has been substantially limited, primarily due to the tumor's distinct immune-evasive characteristics and a suppressive tumor microenvironment (TME). This review systematically examines the multiple mechanisms underlying immunotherapy resistance in UM, including low tumor mutational burden, immune checkpoint overexpression, metabolic adaptations, and the epigenetic silencing of immune-stimulatory genes. Additionally, we analyze emerging strategies aimed at modifying the TME to enhance immune recognition and response, which include targeting suppressive immune cell populations, addressing metabolic and hypoxic barriers, and utilizing epigenetic modulators to restore immune activation pathways. Furthermore, we highlight recent advances in identifying predictive biomarkers-such as genetic mutations (e.g., BAP1, MBD4), immune gene signatures, circulating tumor DNA, and protein-based blood markers-that may facilitate patient stratification and treatment selection. We also examine novel combination approaches that integrate immune checkpoint inhibitors with targeted therapies, radiation, metabolic interventions, or engineered cellular therapies, several of which have shown promising clinical potential in overcoming UM's inherent resistance mechanisms.Despite persistent challenges, such as toxicity management and limited availability of large-scale trials due to UM's rarity, the integration of multi-omics profiling, precision medicine frameworks, and adaptive trial designs presents new opportunities for therapeutic advancement. This review provides a translational perspective on enhancing immunotherapy efficacy in UM by addressing its unique biology and identifying future directions for clinical innovation.
Keywords: Uveal Melanoma, Immunotherapy resistance, Tumor Microenvironment, predictive biomarkers, immune checkpoint inhibitors
Received: 27 Apr 2025; Accepted: 20 Jun 2025.
Copyright: © 2025 Song, Mou, Song, Chen, Chen and Wei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jian Song, Department of Ophthalmology, Shanghai Changzheng Hospital, Huangpu, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.