# Combating the Immunosuppressive Tumor Microenvironment in Triple Negative Breast Cancer: The Role of Mitochondrial Dynamics in the Polarization of Tumor-Associated Macrophages

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2022 · $51,552

## Abstract

Project Summary/Abstract
Triple Negative Breast Cancer (TNBC) is a devastating disease with aggressive growth and frequent metastases.
Less than 30% of patients with metastatic TNBC survive beyond five years after their diagnosis. While other
breast cancer subtypes have well-defined endocrine markers, TNBC tumors lack such specific therapeutic
targets, making cyclic chemotherapy the mainstay of treatment. Immune checkpoint blockade therapy aims to
leverage TNBC’s inherent yet limited immunogenicity, though success has been restricted by other
immunosuppressive elements in the tumor environment. The overarching goal is to find alternative and/or
synergistic methods to enhance immune-mediated cytotoxicity in the TNBC tumor microenvironment. The overall
objective of this proposal is to enhance tumor microenvironment immunogenicity by repolarizing macrophages
out of a pro-tumor state and into a cytotoxic, anti-tumor state. The central hypothesis is that mitochondrial fusion
governs tumor associated macrophages’ (TAM) pro-tumor functions within the tumor microenvironment. The
rationale for this project is that macrophage metabolism defines polarization fate. Particularly, anti-tumor
macrophages upregulate glycolysis while pro-tumor macrophages depend on oxidative phosphorylation. As
mitochondria house oxidative phosphorylation-associated pathways, and as mitochondrial structure impacts
oxidative phosphorylation efficiency, manipulating mitochondrial structure could determine polarization fate. This
proposal consists of proof-of-principle studies to demonstrate macrophages are flexible and that repolarization
can be achieved by manipulating mitochondrial structure in vitro and in vivo. Along this trajectory, the central
hypothesis will be tested by pursuing two specific aims. Aim 1 will determine the role of mitochondrial dynamics
in macrophage polarization. For this aim, we will culture TNBC tumor macrophages in vitro, manipulate
mitochondrial dynamics, and then evaluate polarization. Aim 2 will determine whether TAM pro-tumor functions
within the tumor microenvironment are dependent on mitochondrial fusion. In this aim, we will evaluate the effect
of macrophages with altered mitochondrial dynamics on T cell cytotoxicity, metastasis, and angiogenesis. The
proposed studies are innovative because they will evaluate direct causation between mitochondrial dynamics
and macrophage polarization and will also define a relevant in vivo macrophage phenotype. The project is
significant because it sets the foundation for manipulation of macrophage mitochondria as a therapeutic strategy
to enhance tumor microenvironment immunogenicity for TNBC. Collectively, these studies will lend insight into
the mechanisms that govern macrophage fate and make progress towards novel immune therapies for TNBC.

## Key facts

- **NIH application ID:** 10386645
- **Project number:** 1F30CA268872-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hilda Lyn Chan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,552
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386645

## Citation

> US National Institutes of Health, RePORTER application 10386645, Combating the Immunosuppressive Tumor Microenvironment in Triple Negative Breast Cancer: The Role of Mitochondrial Dynamics in the Polarization of Tumor-Associated Macrophages (1F30CA268872-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10386645. Licensed CC0.

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