Targeting Tumor Stroma: Current Challenges and Future Directions

ABSTRACT Tumor stroma is a critical component of the tumor microenvironment (TME) that plays a pivotal role in cancer progression and therapeutic response. Beyond providing structural support, stromal components actively regulate tumor growth, metastasis, immune evasion, and drug resistance. Tumor stroma consists of both noncellular elements, particularly the extracellular matrix (ECM), and diverse stromal cells such as cancer‐associated fibroblasts and mesenchymal stem cells. These components collectively form a dense and dynamic barrier that restricts drug penetration, increases interstitial pressure, and promotes an immunosuppressive microenvironment. Despite growing recognition of the importance of stromal biology, a systematic understanding of stromal‐targeted therapeutic strategies and their translational potential remains incomplete. In this review, we comprehensively summarize the biological functions of major stromal components in tumor development and therapy resistance. We further discuss current therapeutic strategies targeting the tumor stroma, including stromal cell depletion, vascular normalization, ECM‐modulating approaches, and emerging nanomaterial‐based delivery systems designed to enhance drug penetration and therapeutic efficacy. In addition, recent progress in preclinical studies and clinical trials of stromal‐targeted therapies is highlighted. By integrating advances in tumor biology, nanomedicine, and translational oncology, this review provides a comprehensive perspective on stroma‐targeted cancer therapy and outlines future directions for precision medicine.