Cordycepin as a Dual-Action Antitumor Agent: A Short Review of Direct Cancer Suppression and Immuno-Oncology Synergy

Cordycepin (3′-deoxyadenosine), a nucleoside analog produced by Cordyceps militaris and related entomopathogenic fungi, has been investigated as a potential dual-action antitumor compound. In preclinical cancer models, tumor-cell proliferation, migration, and metastatic progression have been suppressed through the modulation of oncogenic and metabolic signaling pathways, including c-Myc/Cyclin D1, FGF9–ERK, Akt1, and ERO1α–mTOR–SREBP1. Apoptosis, pyroptosis, and ferroptosis have also been induced in selected cancer models. In parallel, changes in tumor–immune interactions have been observed following cordycepin treatment, including the regulation of PD-L1- and TIGIT-associated pathways, reduced ADAM10 expression, and enhanced NK-cell and CD8 ⁺ T-cell responses. Enhanced antitumor effects have been reported when cordycepin has been combined with immune checkpoint blockade, doxorubicin, temozolomide, photodynamic therapy, or radiotherapy. In addition, stabilized derivatives, adenosine deaminase-resistant prodrugs, aptamer-based platforms, and liposomal formulations have been developed to address the metabolic instability and limited tumor selectivity of native cordycepin. In this short review, recent advances reported from 2023 to 2026 in cordycepin biosynthesis, direct anticancer mechanisms, immuno-oncology modulation, combination strategies, and translational development are summarized.