Venetoclax targets AK2 to remodel the immunometabolic microenvironment in glioma

Gliomas are the most common malignant tumors of the central nervous system and remain largely incurable. Here, we investigated the role of adenylate kinase 2 (AK2) and assessed its potential as a therapeutic target. Integrating multi-omics databases, clinical specimens, in vitro and in vivo functional assays, and structure-based drug screening, we comprehensively characterized AK2 in glioma. AK2 was markedly overexpressed in gliomas, increased with tumor grade, and strongly correlated with poor prognosis. Silencing AK2 suppressed cell proliferation, induced apoptosis, and inhibited tumor growth in orthotopic mouse models. Mechanistically, AK2 sustained mitochondrial metabolism and redox balance, and was associated with an immunosuppressive microenvironment characterized by upregulation of immune checkpoint and HLA molecules and colocalization with M2 macrophages. Structure-based virtual screening identified several candidate inhibitors, with Venetoclax showing the most potent activity. Venetoclax triggered mitochondrial-dependent apoptosis, leading to significant anti-glioma effects in vitro and in vivo. Overall, these findings characterize AK2 as a glioma-associated metabolic and immune-related factor and suggest that AK2 status may contribute to Venetoclax sensitivity. However, the present data do not establish direct AK2 targeting by Venetoclax.