# Metabolic and molecular regulation of myeloid cell functions in brain cancer

> **NIH NIH R01** · WISTAR INSTITUTE · 2024 · $486,185

## Abstract

Glioblastoma (GBM), the most aggressive and lethal form of brain cancer, is characterized by a profound
immunosuppressive microenvironment (TME) that restricts the effects of promising immunotherapies. Therefore,
there is a pressing need to develop more effective interventions to overcome this mechanism of resistance.
Tumor associated macrophages (TAMs) are a mixture of monocyte-derived macrophages (MDM) and microglia
(MG), and they are instrumental for the maintenance of the immunosuppressive state of GBM. However, there
are no effective approaches to overcome the immunosuppressive activity of TAMs in GBM, mainly due to an
incomplete understanding of TAM regulatory functions. Our long term-goal is to dissect targetable metabolic and
molecular mechanisms regulating TAM functions in the context of GBM; as these discoveries will facilitate novel
therapies to target immunosuppression and improve the dismaying outcome of GBM patients. A recent study
demonstrated that TAM are major consumers of glucose and maintain a robust glucose metabolism in the TME.
However, it has not yet been determined how GBM supports the adaptation to glucose metabolism in TAMs
and the functional consequences of this adaptation also remain elusive. Endoplasmic reticulum (ER) stress
activation is associated with the malignant progression of glioma and with the infiltration of anti-inflammatory
macrophages. PKR-like ER kinase (PERK), a critical ER stress sensor, was found to be significantly activated
in human glioma tissues, and its inhibition altered ATP/lactate production by glioma cells. Our preliminary data
expanded these findings indicating that MDM demonstrated highest glucose avidity among MG and neoplastic
cells in GBM tumors, and PERK was strongly activated in GBM infiltrating GLUT1+MDM. Contrary to MG, MDM
exhibited potent immunosuppressive activity. GLUT1+MDM were the only contributors to the suppressive activity
associated with MDM in GBM tumors. GBM-derived factors primed activation of PERK signaling in MDM, which
correlated with metabolic reprogramming resulting in high glycolysis, immunosuppressive functions, histone
lactylation, and no change in histone acetylation. Based on our crucial observations, we hypothesize that a
PERK-driven perturbation of glucose metabolism in MDM governs their immunosuppressive functions via
lactate-derived lactylation of histone lysine residues. We will test this hypothesis through the following aims:
Aim1: to elucidate underlying mechanisms of how PERK governs glycolysis in MDM in GBM tumors; Aim2:
to define glucose-driven epigenetic modifications that regulates immunosuppressive programs in MDM;
Aim3: to investigate the therapeutic potential of an epigenetic targeting approach to modulate the functions
of TAMs in GBM. The proposed studies are highly innovative because they will elucidate a previously
uncharacterized link between ER stress and glucose metabolism that regulates the activity of TAMs via
epigenetic mechanisms. Our p...

## Key facts

- **NIH application ID:** 11058866
- **Project number:** 7R01NS131912-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Filippo Veglia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $486,185
- **Award type:** 7
- **Project period:** 2023-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11058866

## Citation

> US National Institutes of Health, RePORTER application 11058866, Metabolic and molecular regulation of myeloid cell functions in brain cancer (7R01NS131912-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11058866. Licensed CC0.

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