# Sustaining antitumor effector CD8+ T cells for cancer therapy

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $633,355

## Abstract

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. It has been
reported that terminally differentiated exhausted T cells display impaired mitochondrial respiration
and/or glycolysis and such limited metabolic reserve reinforces T cell dysfunctionality especially
in the tumor microenvironment of advanced cancer. The molecular mechanism by which
sustaining metabolic fitness in highly differentiated effector T cells (TEFF) for enhancement of anti-
tumor immunity has been ill-defined. Interestingly, increased levels of glutathione (GSH) are
observed in the majority of tumors such as breast cancer and melanoma contributing to cancer
progression and treatment resistance in part by preventing glutathione peroxidase 4 (Gpx4)
dependent ferroptosis, an iron-dependent programmed cell death. However, the role of the GSH-
Gpx4 metabolic axis in modulating the antitumor response of CD8+ T cells remains elusive. Based
on the preliminary results we obtained, the central hypothesis is that sustaining the GSH-Gpx4
axis while inactivation of adenosine A2A receptor (A2AR) is critical for the generation of long-lived
TEFF for durable metabolic responses against tumor cells, and bioengineering TEFF to conditionally
express Gclc/Gpx4 with A2AR inhibition improves in vivo persistence and function to prolong the
efficacy of adoptive cell therapy (ACT). To test this hypothesis, we will define the downstream
metabolic and cellular effects of sustaining the GSH-Gpx4 axis while inactivation of A2AR
signaling in TEFF cells, and further determine the safety and efficacy of adoptive therapy of murine
and human T cells bioengineered to express Gclc/Gpx4 with A2AR inhibition.

## Key facts

- **NIH application ID:** 10901473
- **Project number:** 1R01CA290743-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** WEIGUO CUI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $633,355
- **Award type:** 1
- **Project period:** 2024-05-17 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901473

## Citation

> US National Institutes of Health, RePORTER application 10901473, Sustaining antitumor effector CD8+ T cells for cancer therapy (1R01CA290743-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10901473. Licensed CC0.

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