Abstract
Background: Cordycepin (COR) is a natural nucleoside analogue extracted from Cordyceps fungi, attracting significant attention for its multi-targeted antitumor activity.
Objective: This paper systematically reviews COR's chemical structure, isolation and purification methods, and its four major antitumor mechanisms: inducing apoptosis, arresting cell cycle progression, inhibiting invasion and metastasis, and modulating the tumor immune microenvironment. Additionally, this paper analyzes the potential and limitations of COR as a monotherapy, along with its synergistic strategies and prospects for combination therapy. Methods: Relevant preclinical and mechanistic studies addressing COR structure, production and purification, antitumor activity, tumor immune modulation, and combination therapeutic strategies were reviewed and synthesized.
Results: COR exhibits antitumor activity through multiple complementary mechanisms. It induces apoptosis by activating mitochondrial and death-receptor-associated pathways, including Bax/cytochrome c/caspase signaling and JNK-mediated caspase activation. COR also inhibits tumor cell proliferation by inducing predominantly G2/M cell-cycle arrest through modulation of CDK1 and cyclin B1. In addition, it suppresses tumor migration and invasion by inhibiting epithelial–mesenchymal transition, FAK/Akt signaling, and matrix metalloproteinases. COR further modulates the tumor immune microenvironment by enhancing antitumor immune responses, promoting T-cell infiltration and macrophage-mediated tumor-cell phagocytosis, and regulating immune checkpoint-related pathways such as CD47 and PD-L1. Preclinical studies indicate potential synergistic effects when COR is combined with chemotherapeutic agents, including cisplatin, gemcitabine, and doxorubicin, as well as immune checkpoint inhibitors.
Conclusion: COR is a promising multi-mechanistic natural compound with substantial preclinical potential for cancer therapy. However, poor solubility, low oral bioavailability, rapid metabolism, short systemic half-life, production challenges, and limited clinical evidence remain major barriers to translation. Future studies should focus on pharmacokinetic optimization, targeted delivery, biomarker identification, mechanistic validation, and well-designed clinical trials to establish the safety and therapeutic efficacy of COR.