Metabolic sovereignty through oxidative hostility: a mechanistic perspective on how cancer engineers stromal...

Cancer cells orchestrate a profound remodeling of their microenvironment to suppress immune surveillance and create metabolic dependency in surrounding stroma. We propose a mechanistic hypothesis in which this transformation is driven by a coordinated reactive oxygen species (ROS) signaling cascade. Cancer cells generate superoxide (O₂•^-) through NADPH oxidase (NOX) upregulation and mitochondrial respiration. Superoxide is rapidly converted to hydrogen peroxide (H₂O₂), a stable, membrane-diffusible ROS species that crosses stromal cell membranes via aquaporin channels. Within cancer-associated fibroblasts (CAFs), H₂O₂ triggers controlled lysosomal membrane permeabilization (LMP), releasing catalytic iron and initiating iron-catalyzed Fenton chemistry that converts this signal into reactive lipid-peroxidation products, which in turn activate PGC-1α and drives a profound shift in CAF metabolism toward fatty acid oxidation (FAO). Through this cascade, CAFs become predominantly FAO-dependent, producing acetyl-CoA, NADPH, and ATP that fuel tumor growth while simultaneously generating a lactate-enriched, acidic, nutrient-depleted microenvironment hostile to immune function. We present three converging lines of evidence supporting this mechanism and provide four experimentally falsifiable predictions, including a critical iron chelation experiment designed as the crucial mechanistic validation of the cascade. If validated, this framework redefines immunotherapy resistance as a metabolic infrastructure problem-not only an immune cell problem-and predicts that targeting stromal metabolic engineering in combination with checkpoint blockade may circumvent resistance in cold tumors.