# Angiotensin II Receptor‐Associated Protein (AGTRAP) Enhances Glioma Cell Survival Through the IL‐6/JAK2/STAT3 Pathway and Correlates With an Immunosuppressive Microenvironment

## TL;DR

AGTRAP promotes glioma cell survival through the IL-6/JAK2/STAT3 pathway and is linked to an immunosuppressive tumor environment.

## Contribution

This study identifies AGTRAP as a novel glioma survival factor linked to IL-6/JAK2/STAT3 signaling and immune microenvironment features.

## Key findings

- AGTRAP expression is elevated in gliomas and correlates with poor survival and adverse clinicomolecular features.
- AGTRAP knockdown reduces glioma cell proliferation and activates apoptosis via suppression of IL-6/JAK2/STAT3 signaling.
- High AGTRAP tumors show a macrophage-rich immune microenvironment and may respond to checkpoint blockade.

## Abstract

There is an urgent need for actionable therapeutic targets for glioma. Angiotensin II receptor‐associated protein (AGTRAP) is upregulated in glioma, but its functional role and downstream programs remain insufficiently defined. This study aimed to clarify the clinical relevance, biological function, and mechanism of AGTRAP in glioma.

AGTRAP expression and clinicomolecular associations were analyzed across public glioma cohorts. Loss‐of‐function studies were performed in glioma cells (A172 and U251), followed by proliferation and apoptosis assays. Recombinant IL‐6 was used for rescue experiments. An orthotopic xenograft model was used to evaluate tumor growth in vivo.

AGTRAP expression is significantly elevated in gliomas versus normal brain tissues and correlates with tumor grade, age, 1p/19q co‐deletion, and IDH mutations. High AGTRAP expression predicted poorer survival. AGTRAP knockdown suppressed proliferation, increased apoptosis, reduced IL‐6 mRNA and protein levels, and attenuated JAK2/STAT3 activation. Recombinant IL‐6 partially restored JAK2/STAT3 signaling and mitigated the growth‐inhibitory phenotype caused by AGTRAP silencing. In vivo, AGTRAP knockdown reduced tumor burden. Transcriptome‐based analyses showed that AGTRAP expression was associated with a myeloid/macrophage‐enriched microenvironment, and exploratory analyses suggested cross‐tumor associations between AGTRAP expression and checkpoint blockade outcomes.

AGTRAP supports glioma cell survival by engaging an IL‐6–linked JAK2/STAT3 program and is associated with a macrophage‐rich, inflammatory tumor microenvironment. These findings suggest that AGTRAP may serve as a candidate intervention target for gliomas.

AGTRAP is upregulated in gliomas and is associated with adverse clinicomolecular features and poor prognosis. Mechanistically, AGTRAP maintains an IL‐6/JAK2/STAT3 survival axis that promotes proliferation and limits apoptosis, and IL‐6 add‐back partially restores JAK2/STAT3 signaling after AGTRAP silencing. AGTRAP‐high tumors also display microglia/macrophage‐enriched immune signatures.