Abstract
RPL18 has emerged as a regulator of tumor behavior beyond its canonical role in protein synthesis. Here, we show that RPL18 enhances melanoma progression and chemoresistance by engaging both intrinsic signaling and the tumor microenvironment. Using melanoma cell lines, patient-derived organoids, and xenograft models, we demonstrate that RPL18 stabilizes BTF3 mRNA, leading to increased BTF3 expression and activation of STAT3 signaling. This pathway promotes melanoma cell proliferation, migration, and resistance to temozolomide. In parallel, RPL18-driven STAT3 activation increases transforming growth factor β (TGF-β) secretion, which induces M2 macrophage polarization and fosters an immunosuppressive microenvironment. Pharmacologic inhibition of STAT3 suppresses RPL18-dependent oncogenic phenotypes and restores temozolomide sensitivity in vitro and in vivo. These findings establish RPL18 as a key coordinator of melanoma progression by linking tumor-intrinsic pathways with microenvironmental regulation. Targeting the RPL18-BTF3-STAT3 axis may improve therapeutic responses in melanoma and other cancers with heightened STAT3 activity.