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Background <p>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.</p> Methods and Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年7月8日

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  • Yuduo Guo,
  • Guanjie Shang,
  • Chao Zhao,
  • Xiaoning Lan,
  • Hongwei Zhang,
  • Ye Cheng

摘要

Background

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.

Methods and Results

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.

Conclusions

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.