PRMT5-Dependent Stabilization of VPS34 Orchestrates Copper Trafficking to Shield Cancer Cells from Cuproptosis and...

Targeting cuproptosis for cancer therapy is hindered by an incomplete understanding of the intrinsic defense networks through which tumor cells mobilize to evade this fate, particularly under therapeutic stress such as radiotherapy. Here, we identify VPS34-mediated copper homeostasis as a critical anticuproptotic process through a genome-wide CRISPR activation screen. PRMT5 directly methylated VPS34 at Arg174 and inhibited K48-linked polyubiquitination and proteasomal degradation of VPS34 by recruiting the deubiquitinase USP10. This stabilization increased the cuproptotic defense of tumor cells by promoting autophagic degradation of the copper importer SLC31A1 and plasma membrane translocation of the exporter ATP7A, thereby reducing the intracellular copper load. Functional analysis and clinical correlation revealed that the PRMT5-VPS34 axis is robustly activated by radiation stress and is necessary for adaptive radioresistance. The inhibition of PRMT5 or VPS34 expression suppressed tumor growth and enhanced the sensitivity of tumors to radiotherapy by unleashing latent copper cytotoxicity both in vitro and in vivo. Together, our findings identify the PRMT5-VPS34 axis as a therapeutic target for sensitizing refractory cancers to radiotherapy.