Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma

In Ewing sarcoma, high SLFN11 expression mediates initial sensitivity to DNA-damaging agents. However, relapse poses a major barrier due to heterogeneous expression or loss of SLFN11 causing therapeutic resistance. Although SLFN11 is established as a predictive biomarker, the mechanisms by which its loss promotes chemoresistance remain poorly understood, creating a critical gap that limits the development of effective treatments. This study shows that loss of SLFN11 induces a distinct metabolic reprogramming in Ewing sarcoma cells. Using integrated transcriptomic, metabolomic, and stable isotope tracing analyses, we identify downregulation of mitochondrial GPD2 and increased glycerophospholipid biosynthesis associated with SLFN11 loss. This study further demonstrates that targeting lipid biosynthesis impairs the viability of SLFN11-deficient cells. Notably, these findings are supported by in vivo data from xenograft models, which reveal elevated choline-derived phospholipid synthesis, suggesting metabolic adaptation in the tumor microenvironment.