Peroxidasin enables melanoma immune escape by inhibiting natural killer cell cytotoxicity.

Peroxidasin (PXDN), an extracellular matrix (ECM)-associated peroxidase, has been implicated in cancer progression. However, its roles in melanoma biology and therapeutic sensitivity remain unclear. Here, we demonstrate that elevated PXDN expression is associated with poor prognosis and reduced survival in melanoma patients. Functional studies revealed that PXDN depletion impairs melanoma cell proliferation, disrupts the cell cycle, and reduces melanoma cell invasive capacities. Furthermore, we found that secreted PXDN modulates anti-melanoma immunity by enhancing melanoma resistance to natural killer (NK)-cell-mediated cytotoxicity. Structural modeling identified a trimeric organization of PXDN, stabilized by disulfide-linked peroxidase domains. Molecular dynamics simulations identified a previously unknown inhibitory interaction between the PXDN N-terminal leucine-rich repeat domain and the NK cell-activating receptor NKG2-D type II integral membrane protein (NKG2D). These findings uncover a redox-independent role for PXDN in promoting immune evasion and tumor progression. Overall, our study highlights PXDN as a critical regulator of melanoma cell biology and a potential therapeutic target for NK-cell-based immunotherapy in melanoma and other solid cancers.