{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T07:15:21Z","timestamp":1791098121087,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    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 (O\n                    <jats:sub>2<\/jats:sub>\n                    \u2022\n                    <jats:sup>-<\/jats:sup>\n                    ) through NADPH oxidase (NOX) upregulation and mitochondrial respiration. Superoxide is rapidly converted to hydrogen peroxide (H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ), a stable, membrane-diffusible ROS species that crosses stromal cell membranes via aquaporin channels. Within cancer-associated fibroblasts (CAFs), H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    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-1\u03b1 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\u2014not only an immune cell problem\u2014and predicts that targeting stromal metabolic engineering in combination with checkpoint blockade may circumvent resistance in cold tumors.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1876377","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:38:03Z","timestamp":1782797883000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Metabolic sovereignty through oxidative hostility: a mechanistic perspective on how cancer engineers stromal dependency via ROS-mediated lysosomal reprogramming"],"prefix":"10.3389","volume":"16","author":[{"given":"Khalid O.","family":"Alfarouk","sequence":"first","affiliation":[{"name":"Alfarouk Biomedical Research LLC","place":["Valdosta, GA, United 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