# Metabolites regulating macrophage function in colorectal cancer

> **NIH NIH R03** · UNIVERSITY OF MINNESOTA · 2024 · $74,274

## Abstract

ABSTRACT
Most colorectal cancer (CRC) patients do not respond to immune checkpoint inhibitor therapies due to poor T
cell infiltration and an immune suppressive environment. The pathological characteristics of CRC are unique due
to the complex microbiome in the tumor microenvironment. Diverse bacterial species and metabolites in the
tumor can alter the activity and function of infiltrating immune cells, regulating the tumor's immune environment.
Therefore, understanding how tumor-enriched metabolites change the immune environment is crucial for
developing novel microbiota/metabolite intervention approaches.
We observed that macrophages resembling an M2-like phenotype are in a higher proportion in CRC samples
compared to patient-matched normal tissues. Our metabolomic analysis of CRC tissues showed increases in
essential amino acids, which strongly correlate with altered macrophage phenotype. Further, monocytes
exposed to tumor-enriched metabolites such as tryptophan and phenylalanine increase markers associated with
immunosuppressive macrophages. However, whether microbial-derived metabolites alter macrophage
polarization and contribute to immunosuppressive phenotypes, which can influence the immune environment in
CRC, remains unknown. We hypothesize that altered enrichment of metabolites in CRC correlates with
immunosuppressive macrophages and that critical tumor-enriched metabolites modulate the macrophage
phenotypes. In Aim 1, we will assess the impact of tumor-enriched metabolites on macrophage phenotype. In
Aim 2, we will functionally validate key metabolites influencing macrophage polarization in CRC organoid
coculture models.
We will use a metabolite screening approach using human primary peripheral blood mononuclear cells from
healthy donors and CRC patients to assess whether tumor-enriched metabolites can promote
immunosuppressive macrophage phenotypes. In addition, we will use human microsatellite stable and
microsatellite instable CRC organoids cocultured with patients matched undifferentiated monocytes and tumor-
enriched metabolites to assess shifts in macrophage subtypes. We will identify critical metabolites that can alter
macrophage phenotype and function, contributing to a sustained immunosuppressive tumor environment.
Impact. Determining interactions between tumor-enriched metabolites and macrophage phenotype will increase
the clinical implications of this study by solidifying the premise that the immune environment can be manipulated
by endogenous metabolic regulation.

## Key facts

- **NIH application ID:** 10875586
- **Project number:** 5R03CA282844-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Subbaya Subramanian
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $74,274
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875586

## Citation

> US National Institutes of Health, RePORTER application 10875586, Metabolites regulating macrophage function in colorectal cancer (5R03CA282844-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875586. Licensed CC0.

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