Metabolic Flexibility in Cancer: How Diet and Nutrition Shape Tumor Survival and Resistance

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.

Introduction
Key metabolic pathways involved in cancer
How flexibility enables resistance
Dietary approaches to overcome metabolic flexibility
Glucose restriction and the keto diet
Targeting amino acid metabolism
Future research directions
References
Further reading

How exploiting the metabolic adaptability of tumors through targeted dietary strategies could open new avenues to overcome resistance and improve cancer therapy outcomes.

Image Credit: Lightspring / Shutterstock.com

Introduction

Metabolic flexibility in cancer is defined as the ability of tumor cells to selectively utilize different energy sources, such as glucose, lactate, glutamine, fatty acids, and acetate. This adaptability supports cancer survival and progression in hypoxic and nutrient-limited regions of the tumor microenvironment by enabling tumor cells to shift between available substrates and metabolic routes. Related to flexibility, “metabolic plasticity” describes the ability to process the same nutrient in different ways (for example, routing glucose toward energy production rather than biosynthesis), thereby further expanding tumor adaptability. These features can also influence host and immune cell function in the tumor microenvironment, as tumor-driven metabolic byproducts (e.g., lactate) and nutrient competition can suppress anti-tumor immunity.^1,2

Key metabolic pathways involved in cancer

A unique property of cancer cells is their ability to undergo metabolic reprogramming, during which they preferentially utilize aerobic glycolysis, glutaminolysis, mitochondrial respiration, and other metabolic pathways to support survival and proliferation. Oncogenes, tumor suppressor genes, and other metabolic regulators orchestrate metabolic reprogramming to resist cell death from both intrinsic and extrinsic factors, as well as to adapt to hypoxic and nutrient-deficient conditions in the tumor microenvironment (TME).²   

During aerobic glycolysis, which can constitute ~56%–63% of ATP production in many cancer cells, excess glucose from the surrounding environment is metabolized to lactate, even in the presence of oxygen. Cancer cells also exhibit increased glutamine metabolism, a phenomenon often described as ‘glutamine addiction,’ during which additional carbons and nitrogens are produced to further support cell growth and survival.²

These metabolic alterations can help meet bioenergetic and biosynthetic demands while also contributing to an immunosuppressive TME. Elevated lactate and other byproducts can acidify the TME and inhibit immune effector function, while tumor nutrient consumption can deprive immune cells of glucose and amino acids needed for activation and proliferation.²

How flexibility enables resistance

Metabolic plasticity and flexibility in cancer cells are key contributors to treatment resistance, in part because tumors contain metabolically heterogeneous cell populations and experience changing gradients of oxygen and nutrients. Under therapeutic pressure, resistant clones can emerge that compensate by increasing glycolysis, relying more heavily on oxidative phosphorylation (OXPHOS), or switching nutrient sources depending on what is available in the microenvironment.¹ 

For example, resistant tumor states can show increased reliance on OXPHOS rather than glycolysis, including in melanoma, where elevated OXPHOS in resistant clones has been linked to PGC-1α and oxidative stress buffering. Notably, combining MAPK pathway inhibition with mitochondrial-targeting agents (e.g., Gamitrinib) has been explored preclinically to counter bioenergetic compensation and improve response in melanoma models.¹

Flexibility is also shaped by the tumor microenvironment and stromal nutrient support. For instance, stromal cells can provide metabolites that fuel tumor growth, and tumor adaptation can be reinforced by microenvironmental processes such as autophagy and exosome release that supply amino acids, fatty acids, and nucleic acids under stress. Cancer cells can additionally develop resistance when therapies exploit a metabolic vulnerability: tumors with ASS1 silencing (rendering them arginine-auxotrophic) can acquire resistance to arginine-depleting approaches through re-expression of ASS1, including via MYC binding to the ASS1 promoter.¹

Dietary approaches to overcome metabolic flexibility

In addition to targeted therapies and immunotherapies, lifestyle interventions and dietary modifications tailored to individual metabolic profiles may complement standard cancer treatments and improve therapeutic outcomes.³”

Several dietary strategies have been proposed and are currently being investigated for their therapeutic benefits against cancer. Many of these interventions involve caloric restriction through fasting or a fasting-mimicking diet in an effort to alter systemic nutrient and growth-factor signaling, including reductions in circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1) levels, alongside stress-response programs such as AMPK activation and autophagy induction.³

Glucose restriction and the keto diet

The increased demand for glucose by cancer cells has supported investigation into various dietary approaches, such as reduced fructose intake or mannose supplementation, for their potential to modulate tumor metabolism and, in some settings, restrict tumor growth. Similarly, the ketogenic diet, characterized by high fat and very low carbohydrate intake, can lower circulating glucose and function as an “insulin-suppressing” diet, often reducing insulin and IGF-1 signaling, which can otherwise promote tumor growth pathways. Ketogenic diets increase hepatic production of ketone bodies (e.g., acetoacetate and β-hydroxybutyrate), which peripheral tissues can convert to acetyl-CoA to fuel the TCA cycle.³

Importantly, responses to ketogenic diets are heterogeneous across tumor types and models. Restricting glucose can force greater reliance on mitochondrial metabolism, which may increase reactive oxygen species (ROS) to toxic levels in some highly glycolytic tumors, but other tumors may show reduced oxidative stress or even use ketone bodies effectively, depending on ketolytic capacity.³ Accordingly, preclinical and clinical results are mixed, and ketogenic diets are generally viewed as more plausible as adjuvants than as stand-alone therapies.³

Targeting amino acid metabolism

Dietary approaches that isolate specific amino acids have also been investigated for their potential to impact cancer cell survival, both alone and in combination with different therapeutics. Because tumor amino acid dependencies vary by tissue context and genotype, interventions are increasingly framed as “precision nutrition” strategies that aim to match nutrient modulation to tumor metabolic vulnerabilities.³

Arginine limitation provides a well-studied example of a genotype-linked vulnerability. Several cancers show loss of argininosuccinate synthase 1 (ASS1), which makes them dependent on exogenous arginine and potentially sensitive to arginine depletion strategies (including pharmacologic arginine-degrading enzymes). However, resistance can emerge through metabolic remodeling, including re-expression of ASS1 in tumors that were initially ASS1-low. Diet-based arginine restriction has shown activity in some animal models, but clinical evidence for dietary arginine depletion as a therapeutic strategy remains limited and context-dependent.³

Methionine restriction has also been investigated as a way to stress tumor metabolism. In preclinical work, dietary methionine restriction sensitized colorectal cancer patient-derived xenograft models to chemotherapy (e.g., 5-fluorouracil).¹ Because prolonged restriction of essential nutrients may be difficult to tolerate, short-term or cyclic approaches are often considered to improve feasibility.³

Dietary proteins are the primary sources of amino acids for cancer cells, which has led to the investigation of protein restriction strategies to inhibit tumor growth. In humans, observational evidence has linked lower protein intake with reduced circulating IGF-1 and lower cancer and overall mortality in adults aged 65 and younger, with different (and less clearly beneficial) associations in older adults, emphasizing that age, baseline nutritional status, and treatment context matter when considering protein restriction.³

Future research directions

The combination of dietary approaches with modern therapeutics has emerged as a promising strategy to overcome resistance to these drugs. For example, upregulation of the phosphoinositide 3-kinase (PI3K) pathway is frequently observed in cancer, which has led to the development of several PI3K inhibitors, many of which are associated with limited efficacy as a monotherapy. However, PI3K inhibition can trigger hyperglycemia and a compensatory insulin surge that reactivates PI3K signaling in tumors, and preclinical studies showed that a ketogenic diet blunted this insulin feedback and improved survival in PI3K-driven tumor models. Clinical trials investigating this combination strategy have been initiated, supporting the need for careful patient selection and monitoring.³

“Recognizing cancer dynamic metabolic adaptability as an entity can lead to targeted therapy that is expected to decrease drug resistance.”¹

Despite extensive research elucidating the roles of key cellular metabolic processes in cancer development and their enabling of growth and survival, additional research is needed to understand how microenvironmental heterogeneity, stromal nutrient support, and immune-metabolic interactions shape metabolic flexibility and dietary response. Future work will likely benefit from integrating tumor genotype, tissue environment, and systemic host responses to diet to identify which patients are most likely to benefit and to avoid interventions that could be harmful in specific contexts.³

References

1. 1. Fendt, S. M., Frezza, C., & Erez, A. (2020). Targeting metabolic plasticity and flexibility dynamics for cancer therapy. Cancer Discovery 10(12); 1797-1807. DOI: 10.1158/2159-8290.CD-20-0844. https://aacrjournals.org/cancerdiscovery/article/10/12/1797/2664/Targeting-Metabolic-Plasticity-and-Flexibility
   2. Aden, D., Sureka, N., Zaheer, S., et al. (2024). Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment. Immunology. DOI: 10.1111/imm.13871. https://onlinelibrary.wiley.com/doi/10.1111/imm.13871.
   3. Tajan, M., & Vousden, K. H. (2020). Dietary Approaches to Cancer Therapy. Cancer Cell 37(6); 767–785. DOI: 10.1016/j.ccell.2020.04.005. https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30204-X

Further Reading

• All Cancer Content
• Cancer Plasticity: The Shape-Shifting Threat Challenging Modern Treatments
• What is Cancer?
• What Causes Cancer?
• Cancer Glossary

Last Updated: Jan 5, 2026