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Landscape analysis of tumor metabolic plasticity spanning different cancer types, in particular, metabolic crosstalk within cell subpopulations, remains scarce. Therefore, we proposed a new in-silico framework, termed as MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to depict tumor metabolic plasticity based on transcriptome data. Next, we performed an extensive metabo-plastic analysis of over 6000 tumors comprising 13 cancer types. The metabolic plasticity within distinct cell subpopulations, particularly interplay with tumor microenvironment, were explored at single-cell resolution. Ultimately, the metabo-plastic events were screened out for multiple clinical applications via machine learning methods. The pilot research indicated that 6 out of 13 cancer types exhibited signs of the Warburg effect, implying its high reliability and robustness. Across 13 cancer types, high metabolic organized heterogeneity was found, and four metabo-plastic subtypes were determined, which link to distinct immune and metabolism patterns impacting prognosis. Moreover, MMP3C analysis of approximately 60\u00a0000 single cells of eight breast cancer patients unveiled several metabo-plastic events correlated to tumorigenesis, metastasis and immunosuppression. Notably, the metabolic features screened out by MMP3C are potential biomarkers for diagnosis, tumor classification and prognosis. MMP3C is a practical cross-platform tool to capture tumor metabolic plasticity, and our study unveiled a core set of metabo-plastic pairs among diverse cancer types, which provides bases toward improving response and overcoming resistance in cancer therapy.<\/jats:p>","DOI":"10.1093\/bib\/bbad471","type":"journal-article","created":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T02:09:05Z","timestamp":1703556545000},"source":"Crossref","is-referenced-by-count":9,"title":["MMP3C: an<i>in-silico<\/i>framework to depict cancer metabolic plasticity using gene expression profiles"],"prefix":"10.1093","volume":"25","author":[{"given":"Xingyu","family":"Chen","sequence":"first","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology , Taipa, Macao SAR 999078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Deng","sequence":"additional","affiliation":[{"name":"CRDA , Faculty of Health Sciences, , Taipa, Macau SAR 999078 , China"},{"name":"University of Macau , Faculty of Health Sciences, , Taipa, Macau SAR 999078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Wang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology , Taipa, Macao SAR 999078 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7092-7587","authenticated-orcid":false,"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Dr. Neher\u2019s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, 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