The Influence of Metabolism in the Tumor Microenvironment

The tumor microenvironment (TME) is a harsh environment shaped by nutrient scarcity, hypoxia and unfavorable pH levels. To survive in such hostile conditions, cancer cells reconfigure their metabolism, increasing their consumption of glucose and amino acids to enable tumor growth and cancer progression. In this article, we explore how the metabolic constraints of the TME influence cancer and immune cells and dive into the metabolic cross-talk between them.

Metabolic constraints in the TME 

Solid tumors have dysfunctional vasculature that affects the delivery of nutrients to the TME. This limited availability of nutrients, including glucose, oxygen and amino acids, drives nutrient stress in the TME, which influences cancer growth and progression.  

In response to metabolic stress, cancer cells can drive changes in their motility machinery, leading to increased migration, invasion and metastasis.

A lack of nutrients can also increase cytoprotective metabolism in cancer cells, protecting them from damage. For example, by amplifying the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) – a transcription factor with notable roles in protecting cells against oxidative and metabolic stress – cancer cells can decrease autophagy, promote invasiveness and prevent apoptosis.

“Nutrient constraints do not just impact the metabolism of cancer cells,” Dr. Alexander Muir, assistant professor at the University of Chicago, told Technology Networks. “Anti-tumor immune cells are also challenged by nutrient limitation in tumors.”

Nutrient limitation in the tumor microenvironment can lead to the metabolic suppression of effector immune cells, inhibiting immune-mediated cancer cell killing. In addition, the metabolite differences in the TME can promote regulatory immune cells to drive the immune evasion of cancer cells.

“A lot of studies have really focused on how nutrient stress promotes tumor progression,” said Muir. “However, the nutrient deficits of the tumor microenvironment also challenge cancer cells.”

Cancer cells must adapt their metabolism to survive in the nutrient-poor TME and as these adaptations are not present in normal cells, they could be targeted by drugs to impair tumor growth while leaving normal cells unharmed. “The nutrient stress of the tumor may lead to a whole new set of therapeutic targets,” explained Muir. 

Metabolic cross-talk between cancer and T cells 

Cancer cells do not exist in isolation in the TME, they are usually found in close proximity to immune cells. Such proximity encourages competition for nutrients; when the cancer cells “win”, they starve the immune cells of nutrients critical to their function.  

Both cancer and immune cells need glucose to survive, leading to competition between tumor cells and tumor-infiltrating immune cells. When the cancer cell “outcompetes” the immune cells for glucose, the immune cell is metabolically restricted, leading to dampened immune responses against the tumor, allowing tumor progression.

Tumor cells can also express an enzyme that depletes tryptophan, which further prevents T cell proliferation.

Proximity doesn’t just encourage competition. “In the tumor microenvironment, T cells and cancer cells also sit there in the metabolic by-products and wastes of each other,” explains Muir. “These wastes are functionally important ways that cancers metabolically regulate T cells.”

As a result of their increased metabolism, cancer cells produce more waste products, including lactate and ammonia, which impair T-cell function. Lactate, for example, disrupts the T cell’s ability to maintain aerobic glycolysis.

“Cross-talk where cancer cells overwhelm T cells via competition or waste production are important barriers to immunotherapy,” Muir said.

“T cells also regulate what nutrients cancer cells can get in tumors,” he continued. “There are convincing new studies that T cells control tumors, in part, by limiting the ability of cancer cells to get nutrients important for cell survival.”

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This poses the question as to whether assisting T cells to starve cancer cells of nutrients could help improve the efficacy of immunotherapy. 

Challenges and future directions 

Advances in analytical techniques have “fueled the big boom in cancer metabolism research,” according to Muir. As analytical techniques like nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry continue to develop, the scope of cancer metabolism research will expand as researchers are able to measure the abundance of more molecules in smaller samples. 

“Of equal importance, there have been huge advances in spatial metabolomics,” said Muir. “These technologies will open up new horizons for tumor metabolism research just like large-scale spatial analysis of proteins and RNA molecules have in other areas of cancer biology.”

Physiological techniques are also advancing our understanding of cancer metabolism. “Researchers can now measure nutrients from blood vessels that go into and out of tumors to directly measure what tumors ‘eat’ and what byproducts leave as wastes,” explained Muir.

“One major challenge for the field is thinking about diet,” Muir continued. “There is a huge social need to understand how diet impacts cancer given some dietary patterns are big risk factors for cancer development.”

However, understanding the impact of diet on cancer metabolism is not an easy task, as diet influences metabolism in many ways. “Diet impacts the nutrients that are available to tumors, but also circulating levels of hormones and the immune system and so on,” he said. People also eat very diverse diets, making it difficult to identify which dietary components are key for cancer metabolism.

Dr. Alexander Muir will be presenting at the American Association for Cancer Research 2025 in Chicago, joined by Dr. Cosimo Commisso and Dr. Ilaria Elia, to deliver a session highlighting how new advances in analytical and physiological techniques are driving our understanding of cancer, stromal and immune metabolism in tumors. “I am super excited about our session,” he told Technology Networks. “These new analytical and physiology techniques have really changed how the field thinks about tumor metabolism in the last 5 years.”