Breast cancer remains one of the most formidable challenges in modern oncology, and a growing body of research points to a specialized population of tumor cells as the driving force behind its worst outcomes. These cells, known as breast cancer stem cells, or BCSCs, are capable of initiating new tumors, withstanding chemotherapy and radiation, seeding distant metastases, and re-emerging years after seemingly successful treatment. A new open-access review published in Cellular and Molecular Life Sciences by Eunmi Lee of Yeungnam University College of Medicine and Yibin Kang of Princeton University synthesizes a decade of evidence showing that the remarkable abilities of BCSCs rest on a foundation of metabolic reprogramming, a wholesale rewiring of how these cells generate energy and building material, and on an intimate, bidirectional dialogue with the tumor microenvironment that surrounds them.
The central concept emerging from the review is metabolic plasticity. Unlike many differentiated cancer cells that become locked into a single metabolic strategy, BCSCs can dynamically shift among glycolysis, the rapid but inefficient fermentation of glucose; oxidative phosphorylation, the mitochondrial process that extracts far more energy per glucose molecule; lipid metabolism, which supplies both fuel and membrane components; and amino acid metabolism, which feeds protein synthesis and redox balancing. This flexibility allows BCSCs to maintain their stem-like properties, including self-renewal and the capacity to regenerate an entire tumor, even as oxygen levels, nutrient availability, and signaling conditions fluctuate dramatically within a growing tumor.
Historically, cancer metabolism research was dominated by the Warburg effect, the observation that many tumors prefer glycolysis even in the presence of oxygen. The BCSC literature complicates that picture considerably. Studies cited in the review indicate that stem-like breast cancer cells often rely heavily on mitochondrial oxidative phosphorylation, particularly in populations enriched for markers such as ALDH activity, while more proliferative, non-stem tumor cells tend toward glycolysis. Other work has shown that under hypoxia, hypoxia-inducible factors drive glycolytic enzymes and stemness factors simultaneously, linking a low-oxygen niche directly to the maintenance of the stem-like state. The lesson is that no single metabolic fingerprint defines a BCSC; rather, the fingerprint changes with cellular state and environmental context, and that adaptability is itself a therapeutic problem.
Lipid metabolism has emerged as a particularly important pillar of BCSC biology. Fatty acid oxidation provides abundant ATP and NADPH, helping these cells resist oxidative stress, while de novo lipid synthesis supports membrane expansion during division and the generation of signaling lipids. Enzymes such as acetyl-CoA carboxylase and fatty acid synthase, along with uptake of exogenous fatty acids through CD36, have been implicated in stemness and metastatic potential in breast cancer models. The review emphasizes that lipid handling is not merely a fuel issue: lipid species can influence membrane fluidity, signaling cascades, and even the epigenetic marks that keep stemness programs active, tying metabolism directly to gene regulation.
Amino acid metabolism completes the picture. Glutamine, the most abundant circulating amino acid, feeds the tricarboxylic acid cycle through glutaminolysis, supplies nitrogen for nucleotide synthesis, and supports glutathione production for antioxidant defense. BCSCs, which must endure reactive oxygen species generated by chemotherapy and by their own metabolic activity, appear particularly dependent on such redox-buffering pathways. Serine, glycine, and branched-chain amino acid metabolism have also been linked to tumor initiation and progression in breast cancer, underscoring how the manipulation of nutrient streams beyond glucose shapes the fitness of the most dangerous cells in a tumor.
What elevates the review beyond a catalog of pathways is its insistence that BCSC metabolism cannot be understood in isolation. The tumor microenvironment is a metabolic ecosystem in which adipocytes, cancer-associated fibroblasts, endothelial cells, and immune cells all exchange nutrients and emit paracrine signals that reshape how cancer cells process fuel. In the breast, adipocytes are abundant and can release fatty acids and adipokines that tumor cells readily exploit. Fibroblasts can secrete lactate and alanine that neighboring cancer cells take up as carbon sources, a phenomenon sometimes described as metabolic symbiosis. Endothelial cells lining tumor vasculature influence oxygen and nutrient delivery, while immune cells both compete for nutrients and respond to metabolic signals that can dampen antitumor activity.
The relationship runs in both directions. The review highlights that BCSCs actively remodel their niche to favor tumor initiation, immune evasion, and metastatic colonization. By consuming key nutrients, secreting lactate and other metabolites, and altering extracellular matrix composition, BCSCs can condition their surroundings to suppress cytotoxic T cell function and recruit immunosuppressive cell types. Metabolites themselves act as signaling molecules: lactate, for example, is now recognized as an immunosuppressive oncometabolite, while lipid accumulation in the tumor microenvironment has been associated with dysfunction in antitumor immune cells. This metabolic crosstalk means that targeting BCSC metabolism may simultaneously disarm the protective niche those cells construct around themselves.
Metastasis represents perhaps the most dramatic test of metabolic plasticity. A cancer cell leaving a primary tumor must survive in circulation, endure shear stress and detachment-induced stress, and then colonize tissues with entirely different nutrient and oxygen landscapes, whether bone, lung, liver, or brain. The review discusses how BCSCs and cells with stem-like properties appear pre-adapted for this journey, in part because their flexible metabolism allows them to switch fuel sources as they encounter new microenvironments. At metastatic sites, interactions with resident stromal cells, including osteoclasts in bone or astrocytes in brain, can supply additional metabolic support, illustrating how niche-derived signals continue to govern BCSC behavior long after cells have left the primary tumor.
These insights are now informing therapeutic strategies. The review surveys approaches aimed at metabolic vulnerabilities, including inhibitors of mitochondrial complexes, fatty acid oxidation and synthesis blockers, glutaminase inhibitors, and agents targeting key regulators such as AMPK, mTOR, and hypoxia-inducible factors. Combination strategies that pair metabolic drugs with chemotherapy, endocrine therapy, or immunotherapy are of particular interest, since metabolic rewiring is one route by which BCSCs survive conventional treatment. The authors also acknowledge the challenges: metabolic redundancy means that blocking one pathway often pushes cells onto another, systemic toxicity is a real concern because normal stem cells and immune cells share many of these pathways, and the plasticity that makes BCSCs dangerous also makes them capable of adapting to single-agent metabolic therapies.
The broader message of the Lee and Kang review is that breast cancer should be viewed not just as a genetic disease but as a metabolic and ecological one, in which the fittest cells thrive by continuously renegotiating their relationship with available fuel and with their neighbors. Understanding the interconnected metabolic networks and niche-derived signals that govern BCSC behavior, the authors argue, may enable the development of more effective therapies designed to reduce breast cancer progression and recurrence. As open-access work, the review offers researchers and clinicians alike a comprehensive map of a field that is moving rapidly, and it makes a compelling case that the next generation of breast cancer treatments will need to target not only what cancer cells are, but what they eat, how they breathe, and the company they keep.
Subject of Research: Metabolic plasticity and microenvironmental regulation of breast cancer stem cells
Article Title: Breast cancer stem cell metabolism: metabolic plasticity and microenvironmental regulation
Article References: Lee, E., & Kang, Y. (2026). Breast cancer stem cell metabolism: metabolic plasticity and microenvironmental regulation. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06435-3
Image Credits: AI Generated
DOI: 10.1007/s00018-026-06435-3
Keywords: breast cancer stem cells, metabolic plasticity, tumor microenvironment, glycolysis, oxidative phosphorylation, lipid metabolism, amino acid metabolism, metastasis, therapeutic resistance, immune evasion, cancer metabolism, tumor niche
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Tags: amino-acid metabolismbreast cancer stem cellscancer cell plasticitycancer metabolismcancer metabolism and tumor progressionchemotherapy resistance in breast cancerenergy generation pathways in tumorsglycolysisglycolysis and oxidative phosphorylation in cancerimmune evasionlipid and amino acid metabolism in breast cancerlipid metabolismmetabolic plasticitymetabolic plasticity in cancermetabolic reprogramming in cancermetastasismetastasis initiation by cancer stem cellsoxidative phosphorylationtherapeutic resistancetumor cell adaptation mechanismstumor microenvironmenttumor microenvironment interactionstumor niche
