Chlorogenic Acid in Antitumor Therapy: Multi-Pathway Mechanisms, Nanocarrier-Mediated Smart Delivery, and Synergistic Combinatorial Strategies

Abstract: Malignant tumors remain a global public health challenge with high morbidity and mortality. Conventional therapies are limited by severe adverse effects and drug resistance. Chlorogenic acid (CGA), a widely distributed phenolic compound, has emerged as a promising antitumor agent due to its excellent biocompatibility and multi-targeted bioactivities, including antioxidant, anti-inflammatory, immunomodulatory, and pro-apoptotic. This review systematically summarizes the molecular mechanisms underlying the antitumor activity of CGA, focusing on three core aspects: (1) regulation of key signaling pathways (Janus kinase-signal transducer and activator of transcription (JAK-STAT), Mitogen-Activated Protein Kinase (MAPK), Nuclear factor kappa-B (NF-κB)) in tumor cells; (2) enhancement of host antitumor immune function through immune‑cell activation and cytokine‑network modulation; and (3) induction of tumor cell apoptosis via B-cell lymphoma 2 (Bcl-2) family regulation, oxidative stress, and metabolite synergy. Furthermore, we highlight recent advances in nanocarrier-facilitated delivery of CGA, including metal-based nanocomposites, metal oxide nanoparticles, and functionalized liposomes, and establish a horizontal comparison table to analyze their respective delivery efficiency, tumor accumulation, biosafety and immune activation capacity, which effectively overcome its pharmacokinetic shortcomings, such as short circulation half‑life and poor tumor accumulation. Additionally, synergistic antitumor effects achieved by combining CGA with chemotherapy drugs or immune checkpoint inhibitors across melanoma, lung cancer, colon cancer and hepatocellular carcinoma models are comprehensively discussed. This review provides a comprehensive theoretical foundation for the further development of CGA as a promising antitumor agent and its clinical translation, and outlining operable key challenges and future research directions. Keywords: signaling pathway, immunomodulation, apoptosis, nanodelivery, synergistic therapy, biocompatibility