An OLFM4‐Specific Tumor Subtype of Gastric Adenocarcinoma Exhibits Enhanced Palmitoylation and Energetic Metabolism

As a malignant tumor with high heterogeneity, gastric cancer (GC) still suffers a poor prognosis despite therapeutic advances. For further investigation of its heterogeneity, the single-cell RNA (scRNA) sequencing of human GC samples has been analyzed, which stratifies malignant epithelial cells into seven tumor subtypes. Among these seven subtypes, the C3 tumor subtype characterized by OLFM4 expression shows distinct biological features with enhanced palmitoylation and energetic metabolism, which presents the significant activation of related specific modules, including a palmitoyltransferase of protein palmitoylation, ZDHHC2, and an important transporter of glycolysis named GLUT1. Besides, the functional assays also confirm that the upregulation of expressed OLFM4 could enhance the ATP production in GC cell lines, which indicates elevated energetic metabolism. Moreover, three prognosis-associated genes (MUC16, RALA, PCBD1) are used to establish a prognostic risk model, which could effectively predict the survival of STAD patients and is correlated with the tumor microenvironment (TME) including not only immune checkpoint expression and infiltration of immune cells. These findings not only highlight OLFM4 as a defining biomarker of a metabolically active gastric cancer subtype but also indicate the possibility that targeting palmitoylation and energy metabolism may offer new therapeutic strategies for patients with OLFM4-high gastric tumors.