Metabolic reprogramming is a hallmark of malignancy first recognized a century ago. In some cases, reprogrammed metabolic activities can be exploited to diagnose, monitor, and treat cancer. Stereotyped metabolic activities in cultured cancer cells—notably, aerobic glycolysis, glutamine catabolism, macromolecular synthesis, and redox homeostasis—support the requirements of exponential growth and proliferation. These pathways are under cell-autonomous control by oncogenic signaling and transcriptional networks. This has produced the widespread perception that a core set of fixed metabolic dependencies will prove to be excellent therapeutic targets across diverse cancer types. Several metabolic inhibitors designed to target these pathways have advanced into clinical trials.

The past decade has brought numerous advances in our understanding of why tumors develop metabolic phenotypes that differ from adjacent, nonmalignant tissues and when these phenotypes represent actionable therapeutic vulnerabilities. Mechanistic insights into how the oncogenotype dictates metabolic patterns have exploded, aided by the ever-increasing use of advanced analytical techniques to characterize tumor metabolism in detail. This has led to the remarkable discovery of a few metabolic properties that can directly promote tumor initiation, including the accumulation of D-2-hydroxyglutarate in tumors with mutations in isocitrate dehydrogenase-1 and -2. Other advances have demonstrated the extraordinary amount of metabolic heterogeneity among human tumors and, in some cases, even within distinct regions of the same tumor. This heterogeneity results from a complex set of factors, including processes intrinsic and extrinsic to the cancer cell. Many of these studies have identified promising subtype-selective metabolic vulnerabilities in experimental models. However, they have cast doubt on the classical paradigm of convergent, oncogene-driven liabilities among histologically and genetically diverse tumors. Even more fundamentally, it has become increasingly clear that metabolic phenotypes and vulnerabilities evolve as tumors progress from premalignant lesions to locally invasive tumors to metastatic cancer. Microenvironmental and genetic factors appear to induce selective pressures that drive clonal evolution within tumors, and this can create or eliminate metabolic liabilities while facilitating cancer progression. During metastasis, for example, several studies demonstrate that cancer cells need to activate mechanisms to resist oxidative stress, or else these cells are culled by the oxidizing environment of the bloodstream. A major theme arising from recent research is that pathways that stimulate the growth of localized, treatment-naïve tumors are distinct from and in some cases irrelevant to the activities that drive mortality by supporting metastasis and therapy resistance.

The emerging view of cancer metabolism is that it is flexible and context-specific, with few fixed, broadly applicable liabilities. Understanding how reprogrammed metabolism supports tumor growth—and identifying which reprogrammed activities are most relevant to therapeutic liabilities—requires a more sophisticated view of how metabolic phenotypes evolve as cancer progresses. Advanced animal models that recapitulate the landmark events in human cancer progression will be instrumental in discovering the most important metabolic vulnerabilities. These animal studies will need to be complemented by increasing efforts to assess metabolism directly in human tumors through metabolomics, metabolic isotope tracers, and advanced …