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Metabolic adaptations of brain metastasis

Nature Reviews Cancer volume 25, pages 723–739 (2025)Cite this article

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Abstract

Brain metastases remain a major clinical challenge, characterized by high mortality rates and often limited therapeutic options. The cellular and molecular processes that drive brain metastases are highly intricate, underscored by dynamic metabolic adaptations that enable tumour cells to thrive in the unique microenvironment of the brain. Emerging clinical and preclinical evidence reveals that these metabolic adaptations are not uniform but vary based on the tumour’s tissue of origin, oncogenomic landscape and capacity to endure nutrient stress. Notably, proliferative and dormant metastatic cells within the brain exhibit distinct metabolic profiles, highlighting the complexity of targeting these cells. Key metabolic pathways, including glucose, fatty acid and amino acid metabolism, are co-opted not only to sustain cancer cell survival and growth but also to modulate interactions with resident brain cells, reshaping their function to support metastasis. Importantly, this metabolic heterogeneity underscores the inadequacy of a one-size-fits-all therapeutic approach. Here, we review the adaptive metabolic reprogramming that facilitates brain metastases and discuss emerging strategies to tailor interventions aimed at preventing and treating overt brain metastases.

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Fig. 1: Metastatic cascade in brain metastasis formation.
Fig. 2: Metabolic adaptations during brain metastatic progression.
Fig. 3: Diverse metabolic adaptations in brain metastatic cells.
Fig. 4: Distinct metabolic adaptations in dormant and aggressive brain metastatic cells.
Fig. 5: Metabolic alterations within the microenvironment and their impact on metastatic fitness.

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Acknowledgements

P.K.P. acknowledges support from the Anusandhan National Research Foundation (ANRF/ECRG/2024/002550/LS) and the seed grant from IISER Berhampur. S.M. acknowledges support from ACS (RSG-20-47-01-CSM), Susan G. Komen Career Catalyst Grant (CCR22902470) and NIH/NCI R01CA292390.

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Authors and Affiliations

  1. Department of Biological Sciences, Indian Institute of Science Education and Research Berhampur, Ganjam, Odisha, India

    Pravat Kumar Parida

  2. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

    Srinivas Malladi

  3. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

    Srinivas Malladi

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  1. Pravat Kumar Parida
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  2. Srinivas Malladi
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The authors contributed equally to all aspects of the article.

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Correspondence to Srinivas Malladi.

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PEACE: https://clinicaltrials.gov/study/NCT0300475

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Glossary

[1H]NMR spectroscopy

A powerful analytical technique that uses proton nuclear magnetic resonance to provide detailed insights into molecular structure, distinguishing nearly all hydrogen atoms in organic compounds based on their characteristic chemical shifts.

Adipokine

Cell signalling molecules primarily secreted by adipose tissue that have key roles in regulating the body’s energy and metabolic status.

Autophagic cell death

A regulated form of cell death in which cells degrade their own organelles and cytoplasmic components through the lysosomal pathways.

Blood–brain barrier

A highly selective, dynamic interface that regulates the exchange of molecules between the bloodstream and the central nervous system.

Brain microenvironment

(BME). Complex ecosystem characterized by the presence of specified cell types (astrocytes, microglia and neurons), molecular components (such as neurotransmitters, chemokines and cytokines), metabolic dependencies (high oxygen and glucose demand) and tissue architecture.

Disseminated tumour cells

Cancer cells that break off the primary tumour and travel through the lymph and blood circulation to distant organs within the body.

Fragmented mitochondria

Smaller mitochondrial units resulting from increased mitochondrial fission that is often associated with metabolic reprogramming and adaptation to stress within tumour microenvironment.

Glial cells

Non-neuronal cells in the central nervous system including astrocytes, microglia and oligodendrocytes provide structural and functional support to neurons and help regulate immune and metabolic responses in the brain.

Kynurenine pathway

The primary route of tryptophan catabolism that generates immunosuppressive metabolites such as kynurenine and quinolinic acid, which modulate immune responses.

Metachronous BrM

Refers to metastatic tumours that are diagnosed typically more than 6 months after diagnosis and treatment start of the primary tumour.

Metastatic dormancy

The period during which disseminated tumour cells in distal organs remain dormant or inactive before forming detectable overt metastatic lesions.

Metastatic niche

A dynamic and specialized microenvironment within a distal organ that is shaped by complex interactions among tumour cells, resident stromal cells, immune components, extracellular matrix remodelling and secreted factors and supports the survival, adaptation and potential outgrowth of disseminated tumour cells.

Mitochondrial biogenesis

A process by which new mitochondria are formed within cells through the division of existing mitochondria in response to cellular energy demands and is essential to maintain mitochondrial DNA, mitochondrial mass and energy homeostasis and support cellular functions.

One-carbon metabolism

A network of biochemical reactions comprising both the folate and methionine cycles allows cells to generate one-carbon units (for example, methyl groups) that are essential for biosynthesis of important anabolic precursors and for methylation reactions.

Oxidative carboxylation

A metabolic reaction that occurs under oxidative conditions and requires energy (typically from NAD+ or FAD) to add CO2 to a substrate, often involving decarboxylation-coupled reactions.

Pentose phosphate pathway

A glucose-oxidizing pathway that runs in parallel to glycolysis that generates NADPH and ribose-5-phosphate for anabolic reactions, including nucleotide synthesis and redox homeostasis.

Peripheral neuropathy

A condition resulting from damage to peripheral nerves, often manifesting as pain, tingling or weakness, and can also be induced by chemotherapy.

Pseudotriad synapses

Specialized neuronal synaptic structures involving complex interactions among the presynaptic neuron, postsynaptic neuron and cancer cells that overexpress NMDA receptors.

Reactive astrocytes

Astrocytes in an activated state that is triggered by injury, inflammation or tumour invasion and characterized by morphological changes and upregulation of markers such as glial fibrillary acidic protein.

Redox homeostasis

Dynamic process that maintains the balance between the production and elimination of reactive oxygen species and antioxidants within the cells that are critical to prevent cells from oxidative damage and support cellular function.

Reductive carboxylation

A metabolic reaction that uses reducing equivalents (typically NADPH) to add carbon dioxide (CO2) to a molecule, often a keto acid.

Synchronous BrM

Refers to metastatic tumours that are diagnosed at the same time or within a short period (3–6 months) after the primary tumour is diagnosed.

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Parida, P.K., Malladi, S. Metabolic adaptations of brain metastasis. Nat Rev Cancer 25, 723–739 (2025). https://doi.org/10.1038/s41568-025-00848-1

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