# Metabolic reprograming of fatty acid beta-oxidation to improve cancer immunotherapy

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $413,046

## Abstract

Summary: Metabolic alterations in cancer cells have profound effects in disease development and
progression. In recent years, there has been increasing interest in potential roles of fatty acid β-oxidation
(FAO) in tumorigenesis. While several studies have demonstrated that FAO is crucial for bioenergetic support
of cancer cell growth, there is emerging evidence for potential involvement of FAO in immune modulation.
However, the exact role of this metabolic pathway in antitumor immunity induced by cancer immunotherapy
remains largely unknown. The proposed research seeks to understand the metabolic process of FAO,
centered on its rate-setting enzyme carnitine palmitoyltransferase 1A (CPT1A), as a key contributing factor to
tumor-induced immune dysfunction that impedes cancer immunotherapy. Our preliminary observations
suggest that abnormal elevation in FAO impairs the function of dendritic cells (DCs), which are crucial for
initiation and maintenance of T cell-mediated antitumor immunity. Strikingly, selective ablation of CPT1A in
DCs markedly improves immunotherapeutic potency against established, poorly immunogenic tumors. In this
application, we will use unique genetic tools and molecular/immunological approaches to test the hypothesis
that the CPT1A-depedent FAO pathway defines a tolerogenic phenotype of tumor-associated DCs and
promotes immune suppression (e.g., PD-L1/2) in the tumor microenvironment. We will determine the impact of
DC-intrinsic FAO on cancer immunotherapies, including vaccines or immune checkpoint inhibitors, as well as
mobilization of antigen-specific cytotoxic T lymphocytes (CTLs). Using preclinical mouse models and patient-
derived specimens, we will define the mechanisms underpinning the FAO-impaired antigen-presenting function
of DCs in response to immunostimulatory agents. We will also, for the first time, link this metabolic pathway
functionally to a negative feedback regulator of inflammatory signaling, which can dictate the immunogenicity
of DCs and immune tolerance. Moreover, we will investigate the elevation of FAO in cancer cells as a novel
determinant of their therapeutic resistance to CTLs. Lastly, using the FAO-blocking drugs already approved for
treatment of non-cancerous diseases we will test the concept of metabolic intervention of the FAO pathway to
revitalize immune functions and to sensitize cancer cells to CTLs. Successful completion of this project is
expected to elucidate a previously unrecognized immunosuppressive mechanism involving hyperactive FAO
that promotes immune tolerance in the tumor-bearing host. New insights into this metabolic pathway that
operates in both cancer cells and tumor-associated DCs will advance our understanding of a sub-optimal
response in the majority of patients undergoing cancer immunotherapies. Our finding may open up an entirely
new avenue for improved cancer immunotherapies by reprograming abnormal lipid catabolism to reinvigorate
immune defense against cancer.

## Key facts

- **NIH application ID:** 9857588
- **Project number:** 5R01CA229812-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** XIANJUN FANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,046
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857588

## Citation

> US National Institutes of Health, RePORTER application 9857588, Metabolic reprograming of fatty acid beta-oxidation to improve cancer immunotherapy (5R01CA229812-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857588. Licensed CC0.

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