Macropinocytosis-mediated metabolic reprogramming and therapeutic targeting strategies in cancer

Sang Xiaolin; Cheng Hailing; Liu Pixu

doi:10.16689/j.cnki.cn11-9349/r.2026.02.001

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Electronic Journal of Metabolism and Nutrition of Cancer ›› 2026, Vol. 13 ›› Issue (2) : 173-179. DOI: 10.16689/j.cnki.cn11-9349/r.2026.02.001

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Macropinocytosis-mediated metabolic reprogramming and therapeutic targeting strategies in cancer

¹Sang Xiaolin, ²Cheng Hailing, ¹Liu Pixu

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Abstract

Metabolic reprogramming represents a hallmark of cancer initiation and progression. Accumulating evidence demonstrates that macropinocytosis, a non-selective, high-capacity endocytic pathway, plays a pivotal role in tumor metabolic adaptation. Through membrane ruffling and subsequent macropinosome formation, this process facilitates the internalization of extracellular macromolecules including proteins, lipids, nucleic acids, and necrotic cellular debris. Following lysosomal degradation, these substrates are catabolized into essential metabolic building blocks, including amino acids, fatty acids, and nucleotides, that fuel bioenergetic demands and anabolic processes. This review examines the signaling networks governing macropinocytosis and elucidates its metabolic functions in amino acid, lipid, and nucleotide metabolism. We further describe the bidirectional interplay between macropinocytosis and mitochondrial metabolism, and its contributions to tumor invasion, metastasis, and therapeutic resistance. Two therapeutic strategies targeting macropinocytosis have demonstrated promising efficacy in preclinical studies. Suppression of macropinocytosis deprives tumors of nutrients and alleviates immunosuppression, whereas induction of dysregulated macropinocytosis triggers methuosis-mediated non-apoptotic cell death. Understanding the metabolic dependencies and regulatory circuitries of macropinocytosis will provide foundations for developing metabolism-targeted therapies and precision oncology approaches.

Key words

Macropinocytosis / Tumor metabolic reprogramming / Methuosis / Drug resistance mechanisms / Targeted therapy / Cancer metabolism / Precision treatment

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Sang Xiaolin, Cheng Hailing, Liu Pixu. Macropinocytosis-mediated metabolic reprogramming and therapeutic targeting strategies in cancer[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2026, 13(2): 173-179 https://doi.org/10.16689/j.cnki.cn11-9349/r.2026.02.001

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