Herbal Nanotherapeutics: A Targeted Approach to Modulating the Tumor Microenvironment for Enhanced Antitumor Efficacy

Abstract The tumor microenvironment (TME) is a complex and dynamic network of stromal cells, immune cells, extracellular matrix (ECM) components, and signaling molecules that plays a central role in tumor progression, metastasis, immune evasion, and therapeutic resistance. Targeting TME has emerged as a promising strategy for improving anticancer efficacy. Herbal nanotherapeutic, which integrate bioactive phytochemicals with nanotechnology‐based delivery systems, represent a novel approach for precise and effective modulation of the TME. These nano‐carriers enhance physicochemical stability, bioavailability, pharmacokinetics, and targeted delivery of phytochemicals, thereby facilitating their controlled release and selective interaction with critical TME components. Preclinical studies have demonstrated that herbal nanoparticles inhibit cancer‐associated fibroblast (CAF)‐driven ECM remodeling, reprogram immune cells to augment antitumor immunity, suppress tumor‐associated angiogenesis, and impede tumor growth and metastatic dissemination. Furthermore, they can effectively penetrate hypoxic tumor regions, modulate hypoxia‐inducible factors (HIFs), and induce reactive oxygen species (ROS)‐mediated apoptosis of malignant cells. This review provides a comprehensive analysis of the molecular mechanisms by which herbal nanotherapeutic interact with TME, contributing to the reversal of drug resistance and enhancement of therapeutic outcomes. It also discusses recent advances in nanoparticle design, targeting strategies, and preclinical efficacy, along with critical challenges and their translational potential for clinical application.