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 remains largely unexplored. In this study, we aim to characterize oxidative stress and reduction-oxidation (redox) homeostasis in cutaneous T-cell lymphoma and determine whether increased ROS create a therapeutic vulnerability in malignant T cells and whether they affect neighboring keratinocytes. Lesional mycosis fungoides skin displays increased oxidative DNA and lipid membrane damage and a reduction-oxidation (redox) gene signature distinct from atopic dermatitis, characterized by SOD2 overexpression and PRDX2 repression-a rare redox profile confirmed at the protein level. Primary malignant T cells show widespread cysteine oxidation and constitutively elevated intracellular and mitochondrial ROS. Malignant T cells are selectively killed by 2,3-dimethoxy-1,4-naphthoquinone (and rescued by N-acetyl cysteine), demonstrating that they operate near their maximal antioxidant capacity. Romidepsin-induced apoptosis is similarly N-acetyl cysteine dependent. Supernatants from malignant (but not nonmalignant) T cells induce elevated ROS and recapitulate the SOD2-high/PRDX2-low signature in keratinocytes. This effect is amplified by Staphylococcus aureus activation. Taken together, we find that cutaneous T-cell lymphoma harbors a rare SOD2-high/PRDX2-low redox imbalance and that malignant T cells are sensitive to ROS induction but are able to propagate oxidative stress to keratinocytes.