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

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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.

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