IQGAP2 regulates phagocytic-like activity and PD-L1 expression in glioma through the JAK2/STAT3 axis

Glioma is a highly aggressive central nervous system malignancy characterized by profound immune evasion and therapeutic resistance. Although dysregulated immune programs drive tumor progression, the master regulators linking tumor-intrinsic biological processes to the immunosuppressive microenvironment remain poorly defined. Phagocytosis-related programs, involving cytoskeletal remodeling and membrane dynamics, are increasingly recognized as hallmarks of aggressive cancer phenotypes.

In this study, we integrated large-scale transcriptomic data across multiple cohorts with single-cell RNA sequencing analysis to identify molecular drivers of these programs in glioma. IQGAP2, a scaffold protein essential for cytoskeletal dynamics, was identified as a pivotal factor consistently upregulated in high-grade, IDH-wildtype, and recurrent gliomas. Clinical validation incorporating multivariate analysis and immunohistochemistry confirmed that IQGAP2 expression was an independent prognostic indicator. Functionally, IQGAP2 knockdown significantly impaired the phagocytic-like activity and PD-L1 expression of glioma cells. Mechanistically, IQGAP2 maintained these malignant phenotypes by activating the JAK2/STAT3 signaling pathway, as confirmed by reduced phosphorylation levels upon knockdown and IL-6-mediated pathway rescue experiments.

Our findings characterize IQGAP2 as a novel regulator orchestrating tumor-intrinsic phagocytic-like programs and immune checkpoint modulation, suggesting that targeting the IQGAP2/JAK2/STAT3 axis represents a potential therapeutic strategy to overcome immune evasion in glioma.