Glycolytic Reprogramming era
Otto Warburg established the foundational glycolytic reprogramming paradigm by showing that many tumors take up glucose and convert it to lactate even in the presence of oxygen. Sidney Weinhouse, in the 1950s and 1960s, provided key empirical support by delineating impaired mitochondrial respiration in cancer cells and underscoring the primacy of glycolytic flux. John Cairns, writing in the 1970s, articulated cancer as a metabolic disease driven by altered carbohydrate metabolism and highlighted the glycolytic phenotype as a defining tumor trait. In the imaging and diagnostic arena of the 1980s and 1990s, Michael E. Phelps and colleagues developed FDG-PET to visualize tumor glucose uptake and monitor glycolytic activity, reinforcing this paradigm.
Microenvironmental Immunometabolism era
Representatives shaping cancer metabolism in the microenvironmental immunometabolism era include Claudia M. Commisso, who demonstrated macropinocytosis as a nutrient scavenging pathway in Ras-driven tumors, while Pavlides, Lisanti, and Sotgia advanced the concept of stromal autophagy as a metabolic feed that sustains cancer cells. Stockwell and Dixon defined ferroptosis as a redox-controlled vulnerability linked to cystine uptake, GPX4 activity, and lipid peroxidation, tying redox balance to immune modulation within tumors. DeBerardinis mapped glutamine dependence and alternative fuel pathways in nutrient-poor microenvironments, shaping how cancer cells reprogram metabolism in situ. Kalluri's work on extracellular vesicles and Locasale's insights into one-carbon metabolism and metabolite signaling together illustrate non-cell-autonomous nutrient exchange and metabolic crosstalk that define tumor–immune ecosystem vulnerabilities.