Malignant T Cells Operate at the Edge of Redox Tolerance and Propagate Oxidative Stress in Cutaneous T-Cell Lymphoma

Reactive oxygen species (ROS) are tightly regulated in the skin and implicated in both cancer and inflammatory dermatoses, but the role of oxidative stress in cutaneous T-cell lymphoma (CTCL) remains largely unexplored. Here we aim to characterize oxidative stress and redox homeostasis in CTCL and determine whether increased ROS creates a therapeutic vulnerability in malignant T-cells and whether it affects neighboring keratinocytes. Lesional MF skin display increased oxidative DNA- and lipid-membrane- damage and a redox gene signature distinct from atopic dermatitis, characterized by SOD2 overexpression and PRDX2 repression - a rare redox profile confirmed at protein level. Primary malignant T-cells show widespread cysteine oxidation and constitutively elevated intracellular and mitochondrial ROS. Malignant T-cells are selectively killed by DMNQ (and rescued by NAC) demonstrating they operate near their maximal antioxidant capacity. Romidepsin-induced apoptosis is similarly NAC-dependent. Supernatants from malignant (but not non-malignant) T-cells induce elevated ROS and recapitulate the SOD2-high/PRDX2-low signature in keratinocytes. This effect is amplified by S. aureus activation. Taken together, we find that CTCL harbors a rare SOD2-high/PRDX2-low redox imbalance and that malignant T-cells are sensitive to ROS induction while able to propagate oxidative stress to keratinocytes.