Uveal melanoma as a stress-dependent malignancy governed by a reprogrammable stress-adaptation network.

Uveal melanoma (UM) is a biologically distinct intraocular malignancy with a strong tendency for hepatic metastasis and limited responsiveness to current systemic therapies. Emerging evidence suggests that UM progression is sustained by interconnected stress-response pathways rather than by oncogenic signaling alone. In this Review, we propose that UM is best understood as a stress-dependent malignancy in which GNAQ/GNA11 mutations, BAP1 loss, and sequential ocular-to-hepatic microenvironmental pressures converge on a reprogrammable stress-adaptation network. This network links hypoxia signaling, metabolic plasticity, redox control, proteostasis, and autophagy/mitophagy to metastatic fitness, immune escape, and treatment resistance. We further highlight oxidative stress as a central vulnerability, with moderate reactive oxygen species supporting tumor adaptation whereas excessive ROS may trigger mitochondrial dysfunction, YAP suppression, ferroptosis, and immunogenic cell death. By integrating molecular, metabolic, and ecological perspectives, this framework extends prior UM reviews by identifying stress adaptation as a central organizing principle of UM biology and a source of actionable therapeutic liabilities, including redox regulation, UPR/ISR signaling, mitophagy dependence, and ferroptosis sensitivity.