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 tumor
permissive 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.