Gambogic acid: A review of its pharmacological mechanisms against cancer

Gambogic acid (GA), a caged xanthone derived from the resin of Garcinia hanburyi (known as Téng Huáng in traditional Chinese medicine), has been historically utilized in TCM for its properties of “combating toxins, eroding sores, dispelling blood stasis, and resolving masses” in the treatment of abscesses, boils, and refractory skin diseases. In recent decades, GA has gained significant attention as a promising multi-target anticancer agent. This review aims to synthesize current preclinical evidence regarding GA’s antitumor mechanisms, its efficacy in combination therapies, and strategies to overcome its pharmacological limitations. A systematic literature search was conducted across electronic databases including PubMed, Web of Science, and CNKI to identify relevant preclinical studies investigating the anticancer mechanisms and delivery strategies of GA. Articles were selected based on their relevance to GA’s molecular targets, efficacy in mono- and combination therapy, and novel formulation approaches. Preclinical studies demonstrate that GA exerts broad-spectrum antitumor effects through multiple mechanisms: induction of apoptosis via mitochondrial and death receptor pathways; cell cycle arrest at G0/G1 or G2/M phases; inhibition of angiogenesis via HIF-1α/VEGF/MMPs suppression; and reduction of metastasis through downregulation of MMPs. GA modulates key oncogenic pathways including NF-κB, PI3K/Akt/mTOR, and MAPKs. It overcomes drug resistance by targeting P-glycoprotein, Bcr-Abl, and SHH pathways. Notably, GA induces immunogenic pyroptosis via caspase-3/GSDME activation and reprograms tumor-associated macrophages by suppressing extracellular vesicle-mediated miR-21 transfer. Synergistic effects are observed when GA is combined with chemotherapy, targeted agents ( e.g. , bortezomib, gefitinib), radiotherapy, or photothermal therapy. However, GA’s clinical application is limited by poor solubility and bioavailability. Nanocarrier systems—such as polymeric nanoparticles, protein-based carriers, biomimetic designs, and stimuli-responsive formulations—have significantly improved GA’s stability, tumor targeting, and therapeutic index. GA represents a multi-mechanistic anticancer agent derived from TCM with high translational potential. Despite compelling preclinical results, further well-designed clinical trials are essential to validate its efficacy and safety in humans. The integration of GA with modern drug delivery technologies, especially nanotechnology, provides a promising approach to overcoming its physicochemical limitations. Future research should focus on context-dependent pathway modulation, immune microenvironment interactions, and clinical translation of advanced GA formulations.