Teresa W.-M. Fan, Richard M. Higashi and Andrew N. Lane Center for Environmental and Systems Biochemistry; Markey Cancer Center; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536, USA Correspondence: twmfangmail.com

Stable isotope-resolved metabolomics delineates reprogrammed intersecting metabolic networks in human cancers. Knowledge gained from in vivo patient studies provides the “benchmark” for cancer models to recapitulate. It is particularly difficult to model patients’ tumor microenvironment (TME) with its complex cell–cell/cell–matrix interactions, which shapes metabolic reprogramming crucial to cancer development/drug resistance. Patient-derived organotypic tissue cultures (PD-OTCs) represent a unique model that retains an individual patient's TME. PD-OTCs of non-small-cell lung cancer better recapitulated the in vivo metabolic reprogramming of patient tumors than the patient-derived tumor xenograft (PDTX), while enabling interrogation of immunometabolic response to modulators and TME-dependent resistance development. Patient-derived organoids (PDOs) are also good models for reconstituting TME-dependent metabolic reprogramming and for evaluating therapeutic responses. Single-cell based ‘omics on combinations of PD-OTC and PDO models will afford an unprecedented understanding on TME dependence of human cancer metabolic reprogramming, which should translate into the identification of novel metabolic targets for regulating TME interactions and drug resistance.