# Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2024 · $569,307

## Abstract

Project Summary:
 Metabolic transformation is a hallmark feature of cancer cells that allows sustained anabolic metabolism to
fuel cell growth and proliferation, and when distilled to its core, cancer is ultimately a disease of unchecked
anabolic metabolism. Yet, it is not well understood how the aberrant metabolic activity of tumor cells affects the
function, phenotype and metabolic states of neighboring immune cells in the tumor microenvironment. The
development of new immunotherapies that stimulate anti-tumor T cell responses to control or eradicate cancer
is a revolutionary and promising area of cancer therapy, but the immunosuppressive nature of the tumor
microenvironment remains the biggest obstacle to increasing the frequency of patients that respond to
immunotherapy. We propose that a major component dictating whether the tumor microenvironment (TME) is
immuno-supportive or immuno-suppressive is the metabolic state of tumor cells. This model is based on the fact
that, like tumor cells, tumor infiltrating lymphocytes (TILs) also require high rates of aerobic glycolysis and
glutaminolysis to proliferate and perform tumoricidal effector functions. It is well documented that CD8+ T cells
are functionally suppressed or “exhausted” in tumors and perhaps a primary source of this suppression is simply
nutrient deprivation stemming from competition between metabolically active tumor and immune cells for the
same nutrients. This model of a “metabolic tug-of-war” between tumor and immune cells over nutrients such as
glucose and glutamine presents an entirely different perspective on how an immunosuppressive TME may form.
 To bridge this gap in cancer immunology, we will determine how metabolic pathways, particularly those
involved in lipid homeostasis, utilized by melanoma and pancreatic ductal adenocarcinoma (PDAC) affect the
quality and function of infiltrating immune cells. Specifically, in Aim 1 we will investigate the balance between
lipogenesis and lipolysis in tumor cells to determine how this affects the composition of lipids and lipoproteins in
the TME and the types of TILs present. We will test if CD8+ TILs metabolically adapt to changes in tumor cell
metabolism and learn how this affects their anti-tumor immune response. In Aim 2, we will investigate if TILs
respond to hyperlipidemia and Ox-LDL in the TME via upregulation of the transporter CD36 and elucidate how
Ox-LDL-CD36 signaling suppresses CD8+ TIL effector functions (this work is the first to explore this pathway in
CD8+ T cells to our knowledge). Lastly, we found arachidonic acid (AA) metabolism correlates with TIL infiltration
and in Aim 3 we will explore a new model that the balance of PGD2 and PGE2 changes as tumors progress,
converting an immuno-supportive TME to one that is more immuno-suppressive. In all three Aims we will target
these metabolic pathways to discover novel combinations of therapies that enhance the efficacy of
immunotherapies currently in clinical use today. ...

## Key facts

- **NIH application ID:** 10799658
- **Project number:** 5R01CA240909-05
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Susan M Kaech
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $569,307
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799658

## Citation

> US National Institutes of Health, RePORTER application 10799658, Understanding how metabolic heterogeneity in cancer affects the tumor microenvironment and anti-tumor immunity (5R01CA240909-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10799658. Licensed CC0.

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