# Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $380,262

## Abstract

Project Summary/Abstract
 Despite notable improvements in colorectal cancer (CRC) treatment, the prognosis of patients with
metastatic CRC (mCRC) remains poor, with a median overall survival of approximately 30 months.
Immunotherapy such as immune checkpoint blockade (ICB) represents a novel therapeutic approach for a
variety of cancers including mCRC with microsatellite instability-high (MSI-H). However, ICB therapy shows little
or no clinical activity in approximately 95% of patients with microsatellite-stable (MSS) mCRC. We and others
have shown that administration of either a ketogenic diet (KD) or the ketone body β-hydroxybutyrate (βHB),
enhances the anticancer effects of ICB for CRC in mouse tumor models. However, whether KD/βHB can improve
ICB therapy for CRCs with MSS is not known. Moreover, the impact of altered ketogenesis on the
immunosuppressive tumor microenvironment (TME) remains to be defined and represents a major gap in our
understanding of tumor immunoresistance.
 Cancer associated fibroblasts (CAFs), the major component of tumor stromal cells, play a critical role in the
tumor suppressive TME. We have shown that downregulated ketogenesis is a hallmark in CRC TME. Activation
of oncogenic signaling (e.g., WNT and KRAS) decreases ketogenesis in CRCs. Restoration of ketogenesis
inhibits aerobic glycolytic activity in CAFs and inhibits histone deacetylase 1 (HDAC1)/KLF5 dependent CAF
proliferation and cytokine expression and secretion. Importantly, we showed that KD improves the
immunosuppressive TME, as noted by increased CD8+ T cell and NK cell infiltration and decreased M2
macrophage populations, and enhances the efficacy of ICB. Our findings demonstrate a previously unknown
association of downregulated de novo ketogenesis, metabolic alteration and CAF functions in the TME and have
identified cancer ketogenesis as a potential immunotherapeutic target. Based on these novel findings, we
hypothesize that downregulated ketogenesis contributes to the proliferation and immunosuppressive effects of
CAFs and thus, reprograms the CRC TME, which leads to ICB resistance and CRC progression. Our long-term
goal is to identify aberrant metabolism within the cancer and/or stromal compartments that can be used to
improve the treatment of patients with mCRC. To examine our central hypothesis, we have assembled a highly
collaborative team with significant expertise in CRC progression and treatment, tumor metabolism, tumor
immunity and neoplastic ketogenesis, and planned experiments which will determine the impact of alterations of
ketogenesis on the immunosuppressive TME in CRC, delineate ketogenic control of CAF metabolism,
proliferation, and functional potency in the TME, and define the impact of targeting ketogenic metabolism on the
efficacy of ICB for CRC. Ultimately, our findings will: i) revolutionize our concept of CRC TME and
immunoresistance; ii) significantly advance paradigms regarding the effects of KD/βHB; and iii) may provide a
novel...

## Key facts

- **NIH application ID:** 10914286
- **Project number:** 5R01CA272669-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Bernard Mark Evers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,262
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914286

## Citation

> US National Institutes of Health, RePORTER application 10914286, Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment (5R01CA272669-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10914286. Licensed CC0.

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