Nanodelivery of Traditional Chinese Medicine Monomers: An Emerging Strategy to Reprogram the Immunosuppressive Tumor Microenvironment

Abstract: The tumor microenvironment (TME), a highly complex and dynamic system, plays a central role in tumor progression and resistance to immunotherapy. Key immunosuppressive cell populations within the TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), contribute to immune evasion through complex cytokine signaling and cellular crosstalk. These factors significantly limit the therapeutic efficacy of immune checkpoint inhibitors and other immunotherapies, particularly in “cold” tumors with poor immune infiltration. Traditional Chinese medicine (TCM) monomers have emerged as promising immunomodulatory agents due to their multi-target capability, favorable safety profiles, and ability to remodel the immune landscape. TCM compounds such as curcumin, berberine, resveratrol, and ginsenosides can modulate the recruitment, polarization, or function of TAMs, MDSCs, and Tregs. However, their clinical translation is hindered by the central challenge of poor solubility, low bioavailability, and limited tumor targeting capability. Nanotechnology provides a breakthrough strategy to address this core issue. Recent advances in nanotechnology offer effective solutions by enabling the encapsulation of TCM monomers into nano-delivery systems such as liposomes, polymeric nanoparticles, inorganic carriers, and biomimetic vesicles which enhance drug stability, promote tumor-specific accumulation, and allow controlled release. These integrated systems potentiate the pharmacological effects of TCM agents. Moreover, they help overcome immune resistance mechanisms within the TME. This review systematically examines the immunosuppressive roles of TAMs, MDSCs, and Tregs, summarizes the immunoregulatory actions of TCM monomers, and highlights cutting-edge nano-formulations developed to optimize their delivery. Together, these insights offer a novel framework for developing TCM-based nanomedicine strategies aimed at reprogramming the immunosuppressive TME and enhancing cancer immunotherapy. Keywords: traditional Chinese medicine monomer, nano-delivery systems, tumor microenvironment