Tumor stroma and its role in therapy resistance: mechanisms and therapeutic opportunities.

INTRODUCTION

The tumor microenvironment (TME), composed of cancer, immune, and stromal cells together with the extracellular matrix, plays critical roles in tumor initiation, progression, metastasis, and therapeutic resistance. Although immune-targeted therapies, including immune checkpoint inhibitors and CAR-T cells, have transformed cancer treatment, stromal cells are increasingly recognized as key regulators of tumor biology.

AREAS COVERED: Stromal cells regulate tumor metabolism, immune evasion, angiogenesis, and drug resistance. They originate from surrounding tissues or cellular transdifferentiation and may exert tumor-promoting or tumor-suppressive effects depending on context. Current strategies target stromal components such as hyaluronic acid and laminin for drug delivery or remodel the stroma to improve therapeutic response. Stromal-targeted delivery systems enhance penetration, specificity, safety, and biocompatibility, with promising clinical outcomes. Cancer-associated fibroblasts, mesenchymal stem cells, tumor-associated adipocytes, endothelial cells, and pericytes also represent emerging therapeutic targets. Relevant studies published through April 2025 were identified using PubMed, Scopus, and Web of Science.

EXPERT OPINION: Targeting the tumor stroma represents a promising direction in oncology by improving drug delivery while advancing understanding of tumor biology and treatment resistance, supporting development of more effective, context-specific therapies.