The tumor microenvironment: a key player in multidrug resistance in cancer

Abstract Cancer is the second leading cause of death worldwide. Although multiple new cancer treatments have emerged in recent years, drug therapy, mainly comprising chemotherapy, targeted therapy, and immunotherapy, remains the most common approach. The multidrug resistance (MDR) of cancer cells to various treatments remains a challenge. Scientists have always focused on the acquired drug resistance mechanisms of tumor cells themselves. However, recent evidence shows that the tumor microenvironment (TME) plays a critical role in regulating tumor cell progression, metastasis, immune escape, and drug resistance. In the TME, interactions between cancer cells and non-malignant cells often modify the TME and facilitate drug resistance. Therefore, elucidating this complex interaction mechanism is essential for the development of effective treatments. This review focuses on the role of the TME in promoting chemoresistance in tumor cells through the following mechanisms: (i) inhibiting the immune clearance of tumor cells and facilitating immune escape responses; (ii) stimulating the release of soluble paracrine factors to enhance tumor survival and growth; (iii) promoting survival and altering drug delivery through metabolic reprogramming; (iv) obstructing drug absorption by inducing changes in stomatal cells and blood vessels surrounding the tumor; and (v) inducing the cancer stem cell phenotype. This review also addresses a clinical treatment strategy for targeting the TME, providing insights and a basis for reversing multidrug resistance.