2. Academic Validation
  3. Tumor-intrinsic redox programming drives an SPP1-CD44 axis of immune suppression in uveal melanoma

Tumor-intrinsic redox programming drives an SPP1-CD44 axis of immune suppression in uveal melanoma

  • Redox Biol. 2026 Mar:90:104011. doi: 10.1016/j.redox.2026.104011.
Tongxin Ge 1,  Yun Yang 2,  Wenyue Zhang 1,  Mengyao Li 3,  Xiang Gu 1,  Ludi Yang 1,  Renbing Jia 1,  Xingyun Wang 4,  Xianqun Fan 5,  Ai Zhuang 6
Affiliations

Affiliations

  • 1 Department of Ophthalmology, State Key Laboratory of Eye Health, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, People's Republic of China.
  • 2 Department of Child Health Care, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, People's Republic of China.
  • 3 Department of Ophthalmology, State Key Laboratory of Eye Health, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, People's Republic of China; Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China.
  • 4 Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, People's Republic of China; Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People's Republic of China. Electronic address: [email protected].
  • 5 Department of Ophthalmology, State Key Laboratory of Eye Health, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, People's Republic of China. Electronic address: [email protected].
  • 6 Department of Ophthalmology, State Key Laboratory of Eye Health, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People's Republic of China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, People's Republic of China. Electronic address: [email protected].
PMID: 41534302 DOI: 10.1016/j.redox.2026.104011
Abstract

Uveal melanoma (UM) is a rare yet aggressive malignancy with a high propensity for distant metastasis and poor response to systemic therapies, including immunotherapies. Although recent single-cell studies have uncovered pronounced intratumoral heterogeneity and an immunosuppressive tumor microenvironment, the tumor-intrinsic metabolic programs that drive immune escape remain poorly defined. Here, we performed single-cell RNA Sequencing on primary UM specimens to generate a high-resolution atlas of tumor and immune cell states. We identified a redox-optimized melanoma subpopulation under heavy metabolic-proteostatic demand, characterized by intensive protein secretory activity and elevated antioxidant defenses. This adaptive state is required to sustain the robust secretion of the matricellular protein SPP1, which suppressed the proliferation and function of CD8+ T cells through CD44 engagement. Disruption of redox equilibrium by enhancing Reactive Oxygen Species (ROS) via a mitochondria-targeted Oxidative Phosphorylation Inhibitor triggered endoplasmic reticulum stress and downregulated SPP1 expression, thereby defining a direct metabolic-immune regulatory axis. Together, our findings reveal a previously unrecognized ROS-SPP1-CD44 axis that links tumor redox homeostasis to immune evasion, providing mechanistic insight into the immune-resistant phenotype of UM and suggesting potential therapeutic vulnerabilities within the metabolic-immune crosstalk.

Keywords

Immune evasion; Mitochondrial metabolism; Redox homeostasis; SPP1; Single-cell RNA sequencing; Uveal melanoma.

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