Perspectives from machine learning and multi-omics to decoding the effects of VDAC2 malignant subsets on tumor evolution.

VDAC2's known role in cancer and immune regulation via enhancing the CD8+ T cell-mediated killing, and it is worth systematically digging out the role of VDAC2 in pan-cancer based on this research. Bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomic analyses were utilized to explore the role of VDAC2 from multiple perspectives in pan-cancers. RT-PCR, cell co-culture, CCK-8 assay, Transwell invasion assays, and ELISA were performed to validate the expression level and biological function. VDAC2 was upregulated in the majority of pan-cancers, and functional enrichment analyses displayed that VDAC2 may take part in the biological progress of energy metabolism, mitochondrial damage and cell proliferation. The landscape of VDAC2 expression and immune infiltration was constructed, and the VDAC2-BAK1-IFNγ pathway was identified in digestive cancer. VDAC2 had the potential to serve as a novel prognostic, screening cancer indicator and immune therapeutic target sensitive to various drugs. Overexpression of VDAC2 significantly promoted gastric cancer cell proliferation, invasion and immune invasion, as validated in vitro experiments. In short, our pan-cancer analysis constructed a comprehensive landscape of VDAC2's oncogenic role, establishing VDAC2 + -BAK1-IFNγ as an important pathway in tumor progression and immune evasion. VDAC2 emerges not only as a valuable prognostic biomarker but also as a promising novel therapeutic target.