Cordycepin: Seventy years to the clinic - bridging the translational bottleneck from traditional chinese medicine to first-in-human oncology trial

Background Cordycepin (3′-deoxyadenosine), the principal bioactive constituent of Cordyceps militaris and Ophiocordyceps sinensis - entomopathogenic fungi long valued in traditional Chinese medicine (TCM) as the tonic DongChongXiaCao - was isolated in 1950, making it among the earliest nucleoside analogs identified in the scientific literature. It has since accumulated seven decades of anticancer evidence spanning multiple hallmarks of cancer. Yet no cordycepin-based therapeutic reached regulatory approval until a single recurring pharmacokinetic obstacle was isolated and directly addressed. Objective This review reorganizes the cordycepin anticancer literature around what is termed here the cordycepin translational bottleneck - rapid inactivation by adenosine deaminase (ADA), dependence on Human equilibrative nucleoside transporter 1 (hENT1) for cellular uptake, and rate-limiting intracellular kinase phosphorylation - and traces the successive strategies developed to resolve it. Methods Literature was identified through structured searches of PubMed, Scopus, and Web of Science (1950-2026) using terms combining cordycepin, Cordyceps militaris , and related pharmacological and clinical terms, supplemented by targeted searches for comparator nucleoside-analog oncology drugs. Findings Four overlapping resolution strategies are traced chronologically: ADA-inhibitor co-administration, ADA-resistant structural analogs, nanocarrier-based delivery, and phosphoramidate (ProTide) prodrug chemistry. The last produced NUC-7738 (fosdesdenosine sipalabenamide), which overcomes all three components of the bottleneck simultaneously - ADA-mediated deamination, hENT1 transporter dependence, and rate-limiting intracellular kinase phosphorylation - by delivering cordycepin monophosphate directly into the intracellular space, bypassing the rate-limiting first kinase step that constrains all unmodified nucleoside analogues and has progressed through Phase I/II trials, with evidence of restored anti-tumor immunity when combined with pembrolizumab in PD-1-resistant melanoma. Comparison with four approved nucleoside-analog oncology drugs situates this resolution among precedented and novel translational strategies. Conclusion Although cordycepin was among the earliest nucleoside analogs to be identified, it took nearly seventy years to reach a human oncology trial, a far slower path than another TCM-derived compound artemisinin, that reached patients within the year of its isolation. The translational bottleneck, not the underlying biology, was the central barrier to cordycepin's clinical development; engineering around it via phosphoramidate prodrug (ProTide) chemistry overcomes all three components simultaneously - ADA-mediated deamination, hENT1 transporter dependence, and rate-limiting intracellular kinase phosphorylation - producing the field's first cordycepin derivative to reach human oncology trials.