Mechanistic insights into VSIR-mediated AXL regulation and gastric cancer proliferation.

Gastric cancer (GC) progression is frequently driven by complex tumor microenvironment signals. Here, our study identifies V-set immunoregulatory receptor (VSIR) as a key driver of GC progression via AXL regulation. High-throughput RNA sequencing demonstrated that VSIR overexpression potently induces AXL upregulation in response to lipopolysaccharide (LPS) stimulation. This finding was confirmed through both VSIR overexpression and knockdown experiments. Mechanistically, our data demonstrated that STAT3 directly contributes to AXL transcriptional upregulation. Crucially, VSIR not only enhances LPS induced STAT3 phosphorylation, thereby amplifying AXL transcription, but also interacts with the AXL protein to stabilize it, leading to sustained AXL signaling. Functionally, the VSIR-AXL axis drives GC proliferation; notably, AXL inhibition suppresses this tumorigenesis, while combined AXL and HER2 blockade synergistically abrogates tumor growth. These findings reveal a critical oncogenic pathway and provide a strong rationale for dual-targeted therapeutic strategies in GC management.