Melanoma leverages innate immune IRAK-M signaling to limit metastasis through PTPN22-Induced signaling repression.

Understanding the molecular mechanisms that drive melanoma metastasis within the tumor microenvironment remains a critical objective in cancer research and therapy development. Our study identifies IL-1 receptor-associated kinase M (IRAK-M) as a previously underappreciated regulator of melanoma progression. We found that IRAK-M is either absent or expressed at low levels in human melanomas, and its expression correlates positively with patient survival. To investigate its functional role, we performed RNA sequencing on melanoma cells with restored IRAK-M expression. This analysis revealed PTPN22, a tyrosine phosphatase, as a key downstream effector upregulated by IRAK-M. Notably, PTPN22 expression also correlated with improved clinical outcomes. Functional assays in vitro, in murine models, and in patient-derived samples demonstrated that restoring IRAK-M or PTPN22 expression significantly impaired melanoma cell adhesion, migration, and transendothelial invasion-key steps in metastasis. Mechanistically, IRAK-M induced PTPN22 to dephosphorylate migration-related proteins, including Src family kinases, and reduced matrix metalloproteinase (MMP) secretion and extracellular matrix (ECM) remodeling. Importantly, PTPN22 knockout abrogated the anti-migratory effects of IRAK-M, confirming its essential role in this pathway. These findings establish the IRAK-M-PTPN22 axis as a critical suppressor of melanoma metastasis within the tumor microenvironment and highlight its potential as a therapeutic target to limit tumor dissemination and improve patient outcomes.