Melanoma is an aggressive cancer with high mutational burden and metastatic potential.
Despite this, its extensive molecular rewiring often results in a cold tumor phenotype and
resistance to immunotherapy. RNA-binding proteins (RBPs) have emerged as critical
signaling hubs in this context for their ability to exert pleiotropic effects across multiple
pathways. Among RBPs, spliceosome components are essential and yet, understudied
in melanoma, with a notable lack of in-depth-omics analyses. Our study systematically
profiled splicing factors deregulation during melanoma progression, and identified
DDX46, an essential factor overexpressed in advanced lesions. Through comprehensive
multi-omics analyses, we describe the extensive gene network regulated by DDX46 and
revealed its dual-role in driving oncogenic hallmarks, while concurrently impairing
inflammatory pathways, including NF-κB signaling, uncovering a novel role of DDX46 in
immune modulation. Concordantly, silencing DDX46 in melanoma cells is sufficient to
shift the tumor microenvironment towards a hot state, associating with improved survival
of patients undergoing immunotherapy.