Nanomedicines Reshape the Tumor Microenvironment: Multidimensional Strategies from Modulating “Barriers” to Metabolic Intervention

Xinming Zhao,1,* Dequan Liu,1,* Guandu Li,1,* Wenfei Xu,2 Guangzhen Wu1 1Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Jiaxing, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangzhen Wu, Email wuguang0613@hotmail.com Wenfei Xu, Email xuwenfei.2020@tsinghua.org.cnAbstract: Nanoparticle-driven remodeling of the Tumor Microenvironment (TME) represents a transformative strategy in cancer therapy, shifting from traditional approaches to multidimensional modulation. This review explores how engineered nanoparticles precisely target and alter key TME components—including immune cells (eg, NK cells, dendritic cells, T cells), cancer-associated fibroblasts, and the extracellular matrix—to overcome “Chemical barriers” and “physical barriers”. Furthermore, we highlight the pivotal role of nanoparticles in reprogramming TME metabolism, such as alleviating hypoxia, disrupting the Warburg effect, and modulating lipid and adenosine metabolism. By integrating immune activation with metabolic intervention, nanomedicines not only enhance anti-tumor immunity but also restore metabolic balance, offering a synergistic and potent therapeutic avenue for overcoming treatment resistance and inhibiting tumor progression.Keywords: tumor microenvironment, nanomedicine, metabolic reprogramming, drug delivery