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Seminal randomized controlled trials by Creagan and Moertel administering oral VC (10 g/day) failed to replicate Camerons reported survival benefits in terminal cancer patients, casting doubt on VCs clinical utility ( 2 O 2 generation ( KRAS )-mutant tumor regression, lower doses (510 mM) paradoxically enhance glutathione synthesis in 32% of glioblastoma cases ( TET1 ) -mediated MMP-9 downregulation, yet population studies associate supplemental VC with 1.3-fold increased recurrence risk in ER + breast cancer ( In this review, we synthesize mechanistic insights from redox biology and immunometabolism with clinical trial data to propose a framework for optimizing VC-based combination therapies (Graphical abstract)