Remodeling the Tumor Microenvironment: Mechanistic Insights and Translational Frontiers of TCM-Derived Bioactive...

Recent studies have shown that tumor development and therapeutic resistance are closely linked to the tumor microenvironment (TME), a dynamic ecosystem composed of vascular networks, immune and stromal cells, extracellular matrix components, cytokines, and extracellular vesicles. This review summarizes current mechanistic evidence on how bioactive monomers and purified active fractions derived from traditional Chinese medicine (TCM), including polysaccharides, saponins, alkaloids, terpenoids, flavonoids, and polyphenols, regulate TME-associated processes. These compounds have been reported to modulate macrophage polarization, T-cell and natural killer (NK)-cell surveillance, dendritic-cell maturation, myeloid-derived suppressor cell (MDSC) and neutrophil activities, cancer-associated fibroblast (CAF) activation, angiogenic signaling, cytokine networks, exosome-mediated communication, and extracellular matrix remodeling. However, most available evidence remains derived from cell models and animal experiments, and clinical validation is limited. Therefore, TCM-derived bioactive monomers should currently be interpreted as mechanistic probes, lead structures, or candidate adjunctive agents rather than established TME-directed therapies. Future research should prioritize compound standardization, dose-response relationships, pharmacokinetic and toxicological characterization, reproducible model systems, validated TME biomarkers, and controlled clinical trials.