Nanotechnology-Enabled Reprogramming of the Tumor Microenvironment: Targeting Cancer-Associated Fibroblasts and Immune Suppression

Abstract

The tumor microenvironment (TME) is a dynamic and complex ecosystem composed of malignant cells, stromal components, immune cells, extracellular matrix, and soluble mediators that collectively drive tumor progression, metastasis, and therapeutic resistance. Among its non-malignant constituents, cancer-associated fibroblasts (CAFs) and immunosuppressive immune populations play central roles in shaping a tumorpermissive niche. Conventional anticancer therapies largely target cancer cells directly, often neglecting the stromal and immune context that enables tumor survival and immune evasion. Nanotechnology has emerged as a transformative strategy to overcome these limitations by enabling precise, spatiotemporally controlled modulation of the TME. Nanoparticle-based platforms can selectively deliver drugs, nucleic acids, and immunomodulators to CAFs and immune cells, reprogramming their phenotypes toward tumor-restraining functions. This review critically examines recent advances in nanotechnology-enabled targeting of CAFs and immune suppression within the TME. We discuss the biological rationale for TME reprogramming, design principles of functional nanomaterials, and therapeutic strategies aimed at normalizing fibroblast activity and restoring antitumor immunity. Current challenges, safety considerations, and translational prospects are also highlighted. Collectively, nanotechnology-driven TME modulation represents a promising paradigm shift toward more durable and effective cancer therapies.