Application of hydrogels in 3D tumor microenvironment modeling and drug screening for cervical cancer: A review

Cervical cancer, driven mainly by human papillomavirus (HPV) infection, remains one of the most common malignant tumors among women worldwide, posing significant challenges in treatment and drug development. Traditional two-dimensional (2D) cell culture models fail to accurately replicate the in vivo tumor microenvironment (TME), especially HPV-driven oncogenic signaling, immune contexture, and stromal interactions unique to cervical cancer, limiting their predictive value for therapeutic efficacy (Y. Liu, H. Ai. Comprehensive insights into human papillomavirus and cervical cancer: pathophysiology, screening, and vaccination strategies. Biochim Biophys Acta Rev Cancer. 2024;1879(6):189192). Hydrogels have emerged as promising biomaterials for constructing three-dimensional (3D) tumor models due to their tunable physicochemical properties, excellent biocompatibility, and ability to mimic the extracellular matrix. This review focuses on hydrogel applications in 3D cervical cancer TME modeling, with an emphasis on recapitulating HPV-driven biology, immune-stromal crosstalk, and stromal interactions, emphasizing their role in simulating key aspects of tumor biology such as cell-cell and cell-matrix interactions, hypoxia, and drug resistance. Recent advances in hydrogel-based 3D models for high-throughput drug screening are critically analyzed, highlighting their potential to improve the precision of cervical cancer treatment and accelerate novel drug discovery. However, critical challenges including high cost, limited industrial scalability, technical complexity, and strict regulatory constraints remain to be addressed to realize their full translational potential. By integrating current research findings, this review aims to provide a theoretical framework and technical guidance for future studies focused on enhancing the physiological relevance of in vitro cervical cancer models and optimizing therapeutic strategies.