Integrating MR/SMR prioritization with scRNA-seq highlighted S100P and VSIG2 as downstream candidates; functional assays supported their roles in tumor cell proliferation.<h4>Conclusion</h4>Collectively, these multi-layer data position SPTBN2 as a research-stage prognostic biomarker in CRC and support a mechanistic hypothesis linking SPTBN2-high tumors to immune inhibitory programs. This evidence concerns the gene VSIG2 and neoplasm.