Role of nanotechnology in modulating the tumor microenvironment to enhance immunotherapy efficacy.

The immunosuppressive tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is marked by hypoxia, acidity, and abundant stromal cells, such as cancer-associated fibroblasts, tumor-associated macrophages, and myeloid-derived suppressor cells, along with factors such as tobacco and alcohol exposure, human papillomavirus infection, and microbial imbalance that drive immune evasion and poor immunotherapy responses. This review critically evaluated nanotechnology-driven strategies for reprogramming the OSCC TME, focusing on overcoming immunosuppression, hypoxia, stromal barriers, and OSCC-specific challenges to enhance immunotherapy outcomes. Personalized nanotherapies guided by TME profiling, combination with radiotherapy/chemotherapy, and theranostic nanoparticles show promise despite manufacturing/regulatory challenges. Nanotechnology enables transformative TME reprogramming to potentiate OSCC immunotherapy, necessitating interdisciplinary research and clinical validation.