Interpretation of the Evidence Hierarchy: Several important observations emerge from this classification. First, a significant translational gap exists: despite hundreds of preclinical studies demonstrating synergy, no repurposed non-oncology drug has yet achieved Phase III confirmatory evidence as a combination partner in cancer therapy. Second, the most successful signals (e.g., metformin, valproic acid) share common features: they are mechanistically well-understood, target fundamental hallmarks of cancer (metabolism, epigenetics), and are being evaluated in biomarker-enriched or mechanistically driven trial designs. Third, the CQ experience serves as a cautionary tale, illustrating that robust preclinical autophagy inhibition does not guarantee clinical success without rigorous pharmacodynamic monitoring and patient selection. Collectively, these observations underscore that the path to clinical translation requires not only biological rationale but also trial designs that incorporate predictive biomarkers, pharmacokinetic/pharmacodynamic assessments, and adaptive strategies to identify responsive patient subsets. CAF: cancer-associated fibroblast; CQ: chloroquine; PDTO: patient-derived tumor organoid; TME: tumor microenvironment.