TRAF6 Exerts Tumor‐Promoting Effects via Genetic and Autophagic Modulation in Gastric Cancer

ABSTRACT Autophagy plays a multifaceted role in tumorigenesis. However, the association between genetic variants in autophagy and gastric cancer susceptibility remains unclear. We evaluated the association between single‐nucleotide polymorphisms (SNPs) of autophagy‐related genes and gastric cancer risk using a cohort of 1,625 cases and 2,100 controls. Next, transcriptomic data were used to analyze differential gene expression and characterize the tumor immune microenvironment (TME). Single‐cell RNA sequencing analysis was performed to investigate cell‐type‐specific expression profiles. In vitro gain/loss‐of‐function experiments were conducted to explore the biological roles of TRAF6 in cancer cells. We found that TRAF6 rs5030437 G > A conferred an increased risk of gastric cancer (OR = 1.23, 95% CI: 1.06‐1.43, p = 1.28 × 10 −3 ), particularly in males (OR = 1.24, 95% CI: 1.07–1.44, p = 3.69 × 10 −3 ) and older individuals (OR = 1.41, 95% CI: 1.18–1.68, p = 1.53 × 10 −4 ). TRAF6 expression was significantly upregulated in tumor tissues, correlating with poor prognosis in gastric cancer patients. Enrichment analyses implicated TRAF6 in immune response and inflammation signaling, manifested as its characteristic cellular expression distribution and influence on the abundance of specific immune cells. In vitro experiments demonstrated that TRAF6 positively regulated autophagy activity and promoted cell viability, migration, and proliferation of gastric cancer cells, which were reversed by autophagy inhibition. This study elucidated the genetic association of rs5030437 G > A and gastric cancer as well as the impacts of TRAF6 on TME dynamics and cancer biology, which provided novel insights into gastric carcinogenesis and the tumor ecosystem.