# Metabolic reprogramming to boost the fitness of anti-tumor immunity against metastatic colon cancer

> **NIH CA R37** · COLD SPRING HARBOR LABORATORY · 2026 · $640,583

## Abstract

Abstract
The primary goal of this project is to enhance the efficacy of immunotherapy against metastatic colorectal cancer
(mCRC) by activating the peroxisome proliferator-activated receptor delta (PPARδ)-Carnitine
palmitoyltransferase 1a (Cpt1a) axis in CD8+ T cells. Colorectal cancer (CRC) is among the deadliest cancers
worldwide, with rising incidence and mortality in younger populations. Particularly, mCRC patients, predominantly
of the microsatellite stable (MSS) subtype, show poor responsiveness to current immunotherapies due to the
immunosuppressive tumor microenvironment and low mutation burden that associates with limited
immunogenicity. This creates an urgent need for innovative approaches to boost the immunogenicity and
improve treatment outcomes. Our preliminary studies highlight the role of PPARδ, a lipid-sensing transcription
factor, in modulating the metabolic fitness of CD8+ T cells within the tumor microenvironment, thereby enhancing
their immunogenic potential against mCRC. We found that by promoting mitochondrial fatty acid oxidation (FAO)
through the PPARδ-Cpt1a axis, we could significantly augment the efficacy of existing immunotherapies. The
roles of PPARδ and FAO in tumorigenesis and immunity are controversial due to lack of cell type-specific genetic
loss-of-function and gain-of-function models. We hypothesize that the metabolic competition between cancer
cells and the immune system is a critical determinant of immune cell fitness against cancer. By activating PPARδ
in CD8+ T cells, we aim to tip this balance to enhance immune cell function and thus improve the anti-tumor
efficacy of immunotherapies in mCRC. To achieve our goal, we propose three synergistic aims. First, we will
delineate the specific mechanisms by which PPARδ activation enhances the anti-tumor activity of CD8+ T cells
in the context of MSS mCRC, focusing on their anti-metastatic function and the underlying epigenetic alterations.
Second, we will elucidate the role of Cpt1a-me

## Key facts

- **NIH application ID:** 11309198
- **Project number:** 5R37CA292807-02
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** Semir  Beyaz
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $640,583
- **Award type:** 5
- **Project period:** 2025-04-01T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11309198

## Citation

> US National Institutes of Health, RePORTER application 11309198, Metabolic reprogramming to boost the fitness of anti-tumor immunity against metastatic colon cancer (5R37CA292807-02). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11309198. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*