image: Figure 1. Metabolic reprogramming and exosome-mediated communication within the breast cancer ecosystem.
Credit: ©Science China Press
Breast cancer development is not solely the result of cancer cells acting independently, it involves a dynamic and complex ecosystem composed of cancer cells, immune cells, fibroblasts, adipocytes, and a variety of signaling molecules. Within this intricate environment, two pivotal factors stand out: metabolic reprogramming of tumor cells and the sophisticated communication mediated by exosomes.
Tumor cells drastically alter their metabolic pathways – involving glucose, amino acids, lipids, and iron – to survive and proliferate under the stressful conditions of the tumor microenvironment. Meanwhile, exosomes, vesicles secreted by cells, act as crucial messengers. They carry diverse cargo, including metabolites, proteins, and nucleic acids, transferring information between cells. This intercellular exchange significantly influences the metabolic state of cells within the tumor ecosystem, thereby impacting tumor growth, metastasis, and therapeutic response.
This perspective article emphasizes that exosomes and metabolic reprogramming are not isolated players but engage in a complex, dynamic interplay, forming a critical “exosome-metabolism axis” that fuels cancer initiation and progression. Exosomes directly and indirectly regulate the metabolic activities of recipient cells by delivering metabolism-related molecules. Conversely, the metabolic conditions of the tumor microenvironment – such as low pH, hypoxia, and nutrient scarcity – profoundly affect the biogenesis, cargo composition, and function of exosomes, further shaping this axis.
Figure 1. Metabolic reprogramming and exosome-mediated communication within the breast cancer ecosystem.
This perspective gives particular focus to the role of this axis in breast cancer stem cells (BCSCs), the subpopulation widely recognized as responsible for tumor recurrence and metastasis, and a major contributor to treatment resistance. These “difficult-to-treat” cells demonstrate remarkable metabolic adaptability, flexibly switching between glycolysis and oxidative phosphorylation, and showing unique dependencies on glutamine and lipid metabolism. Furthermore, they employ complex mechanisms to evade ferroptosis (iron-dependent cell death). Crucially, the perspective highlights how exosomes are instrumental in maintaining these challenging characteristics and resistance mechanisms in BCSCs. For instance, exosome-mediated export of ferritin helps BCSCs resist ferroptosis, while exosome-carried signals promote their lipid synthesis and stemness maintenance. Therefore, unraveling and targeting the exosome-metabolism axis within BCSCs is presented as essential for overcoming breast cancer therapy resistance.
Based on this in-depth understanding of the interplay between exosomes and metabolic reprogramming, the article puts forward promising new diagnostic and therapeutic strategies. Exosome-based liquid biopsy techniques offer a non-invasive approach for early diagnosis and prognosis assessment by analyzing exosomal content from body fluids. Targeting the biological processes of exosome formation, secretion, or the specific molecules they carry represents a novel way to disrupt cancer cell communication and suppress tumor progression and metastasis. Furthermore, combining these strategies with drugs that target specific tumor metabolic pathways is proposed as a powerful approach to synergistically enhance therapeutic effectiveness and combat drug resistance.
In summary, this perspective article systematically reviews the significant roles of exosomes and metabolic reprogramming in breast cancer development and progression. It particularly emphasizes the novel insight that their combined interplay crucially regulates the characteristics and resistance of breast cancer stem cells. By outlining future research directions, the article aims to accelerate the development of new diagnostic biomarkers and therapeutic targets based on the exosome-metabolism axis, ultimately offering renewed hope for early, minimally invasive diagnosis and personalized precision therapy for breast cancer patients.