IQGAP2 regulates glioma phagocytic-like activity and PD-L1 expression via JAK2/STAT3 axis

Glioma is an aggressive central nervous system malignancy marked by profound immune evasion and therapeutic resistance. Current treatments often fail due to the tumor's ability to manipulate its microenvironment and escape immune surveillance. Phagocytosis-related programs, involving cytoskeletal remodeling, are increasingly recognized as drivers of aggressive cancer phenotypes. However, the specific molecular regulators linking tumor-intrinsic processes to this immunosuppressive microenvironment remain poorly understood, representing a critical gap in developing effective immunotherapies for glioma.

Researchers integrated large-scale transcriptomic data from multiple cohorts with single-cell RNA sequencing to identify molecular drivers in glioma. They identified IQGAP2 as a pivotal factor. Clinical validation was performed using multivariate analysis and immunohistochemistry on patient samples to confirm prognostic significance. Functionally, IQGAP2 knockdown was performed in glioma cells to assess its impact on phagocytic-like activity and PD-L1 expression. Mechanistic studies investigated JAK2/STAT3 pathway activation via phosphorylation levels and IL-6-mediated rescue experiments.

IQGAP2 was consistently found to be upregulated in high-grade, IDH-wildtype, and recurrent gliomas across multiple transcriptomic cohorts. Clinical validation confirmed that IQGAP2 expression served as an independent prognostic indicator for patient outcomes.

IQGAP2 knockdown in glioma cells significantly impaired both their phagocytic-like activity and their expression of PD-L1. Mechanistically, IQGAP2 maintained these malignant phenotypes by activating the JAK2/STAT3 signaling pathway, evidenced by reduced phosphorylation levels of JAK2 and STAT3 upon IQGAP2 knockdown. Furthermore, IL-6-mediated pathway rescue experiments confirmed the involvement of the JAK2/STAT3 axis in mediating IQGAP2's effects. These findings highlight IQGAP2's role in orchestrating tumor-intrinsic immune evasion.