Xiangying Deng, Xinglong Liu, Lin Zhao
Tumor heterogeneity and therapeutic resistance remain formidable obstacles to effective cancer treatment. Remodeling the tumor microenvironment (TME)-which is characterized by hypoxia, acidosis, immunosuppression, and extracellular matrix (ECM) remodeling-has emerged as a promising strategy to overcome these barriers. In recent years, nanotechnology has enabled the development of multifunctional and stimuli-responsive platforms for targeted TME modulation. Inorganic, organic, and hybrid nanocarriers leverage enhanced permeability and retention (EPR) effects, surface ligand engineering, and responsive elements to achieve spatiotemporally controlled drug and gene delivery. These advanced nanoplatforms can simultaneously normalize tumor vasculature, reverse hypoxia, modulate immune suppression, and degrade the ECM, thereby sensitizing tumors to conventional and emerging therapies. Integrating these TME-oriented strategies with photothermal and photodynamic therapy, immunotherapy, and metabolic reprogramming allows the construction of comprehensive, multimodal treatment systems. Furthermore, the convergence of intelligent nanomaterials and artificial intelligence (AI)-guided precision delivery is fostering the concept of therapeutic ecosystems, which enable dynamic treatment feedback and personalized tumor management. This review systematically summarizes the recent progress in nanotechnology-driven TME remodeling, highlights representative mechanisms and design strategies for multifunctional nanoplatforms, and discusses future opportunities and challenges in the development of intelligent, patient-centric cancer therapy systems.