The tumor microenvironment (TME) plays a critical role in promoting multidrug resistance (MDR) in cancer. This review highlights the mechanisms by which the TME contributes to drug resistance, including immune suppression, paracrine signaling, metabolic reprogramming, and altered drug delivery. The TME consists of tumor cells, immune cells, fibroblasts, and various cytokines, creating an immunosuppressive and nutrient-deficient environment that supports tumor growth and metastasis. Immunosuppressive components such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) contribute to drug resistance by inhibiting immune responses and promoting tumor survival. The TME also promotes metabolic reprogramming, leading to increased drug resistance through hypoxia and altered nutrient availability. Additionally, the TME can hinder drug absorption by altering the structure of the extracellular matrix (ECM) and blood vessels, reducing drug delivery to tumor cells. The TME also supports the development of cancer stem cells (CSCs), which are resistant to conventional therapies. Targeting the TME through immunotherapy, anti-angiogenic therapy, and drug delivery systems is a promising approach to overcome MDR. Clinical trials have shown that combining immunotherapy with anti-angiogenic drugs can enhance therapeutic efficacy and reduce MDR. The review also discusses the potential of targeting TME components such as TAFs and exosomes to improve cancer treatment outcomes. Overall, understanding the role of the TME in MDR is essential for developing effective therapies to combat cancer.The tumor microenvironment (TME) plays a critical role in promoting multidrug resistance (MDR) in cancer. This review highlights the mechanisms by which the TME contributes to drug resistance, including immune suppression, paracrine signaling, metabolic reprogramming, and altered drug delivery. The TME consists of tumor cells, immune cells, fibroblasts, and various cytokines, creating an immunosuppressive and nutrient-deficient environment that supports tumor growth and metastasis. Immunosuppressive components such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) contribute to drug resistance by inhibiting immune responses and promoting tumor survival. The TME also promotes metabolic reprogramming, leading to increased drug resistance through hypoxia and altered nutrient availability. Additionally, the TME can hinder drug absorption by altering the structure of the extracellular matrix (ECM) and blood vessels, reducing drug delivery to tumor cells. The TME also supports the development of cancer stem cells (CSCs), which are resistant to conventional therapies. Targeting the TME through immunotherapy, anti-angiogenic therapy, and drug delivery systems is a promising approach to overcome MDR. Clinical trials have shown that combining immunotherapy with anti-angiogenic drugs can enhance therapeutic efficacy and reduce MDR. The review also discusses the potential of targeting TME components such as TAFs and exosomes to improve cancer treatment outcomes. Overall, understanding the role of the TME in MDR is essential for developing effective therapies to combat cancer.