Targeting SHMT2‐mediated membrane phospholipid remodeling for enhanced anti‐GCSCs treatment

Abstract Cancer stem cells exhibit flexible metabolic profiles. However, the underlying mechanisms for differential metabolic pathways affecting stemness maintenance in gastric cancer are poorly understood. Here, we reveal the role of serine hydroxymethyltransferase‐2 (SHMT2)/serine‐mediated crosstalk between one‐carbon metabolism and lipid metabolism in the stemness maintenance of gastric cancer. Clinically, SHMT2 was significantly highly expressed in Gastric cancer cells (GCs) and gastric cancer stem cells, and was associated with clinical malignant features and poor prognosis in gastric cancer patients. Mechanistically, inhibition of SHMT2 expression resulted in diminished serine levels in one‐carbon metabolism, which subsequently modified the composition and fluidity of membrane phospholipids, leading to a reduction in lipid rafts within cellular membranes. The remodeling of membrane phospholipids hindered the localization of γ‐secretase to lipid rafts, thereby inhibiting the cleavage of CD44 and the subsequent production of CD44‐ICD. Consequently, the transcriptional regulation of c‐Myc and KLF4 by CD44‐ICD was reduced, ultimately disrupting the maintenance of stemness in gastric cancer cells. Together, these results provide compelling evidence for the metabolic adaptability of cancer stem cells, and the SHMT2/serine/lipid rafts signaling axis holds promise as a potential biomarker for the diagnosis and prognosis of gastric cancer. Furthermore, we synthesized HA‐Exo‐si SHMT2 to investigate targeted therapy for GC, offering a novel approach for the clinical treatment of gastric cancer.