The review by Lingnan Meng, Ying Zheng, Hao Liu, and Daiming Fan discusses the critical role of the tumor microenvironment (TME) in promoting multidrug resistance (MDR) in cancer cells. The TME, comprising various components such as immune cells, fibroblasts, and blood vessels, influences tumor progression, metastasis, immune escape, and drug resistance. The review highlights five key mechanisms through which the TME promotes chemoresistance: 1. **Inhibition of Immune Clearance**: The TME facilitates immune escape by modifying the immune response, allowing tumor cells to evade detection and destruction by immune cells. 2. **Soluble Paracrine Factors**: The release of soluble factors enhances tumor survival and growth by modulating angiogenesis, immune suppression, and metabolic pathways. 3. **Metabolic Reprogramming**: Hypoxic conditions in the TME lead to metabolic reprogramming, which can enhance drug resistance through mechanisms like increased expression of P-glycoprotein and altered cellular metabolism. 4. **Alteration of Peritumoral Stomatal Cells and Blood Vessels**: Changes in these structures can obstruct drug absorption and reduce therapeutic efficacy. 5. **Induction of Cancer Stem Cell Phenotype**: The TME can induce the cancer stem cell (CSC) phenotype, contributing to tumor recurrence and resistance. The review also addresses clinical strategies for targeting the TME to overcome MDR, including: - **Targeting the Immune System**: Using immune checkpoint inhibitors and combination therapies to enhance anti-tumor immune responses. - **Targeting Other TME Components**: Developing drug delivery systems and targeting specific components like fibroblasts and blood vessels to improve drug efficacy and reduce resistance. Overall, the review emphasizes the complexity of the TME and the need for a better understanding of its mechanisms to develop effective treatments for MDR cancers.The review by Lingnan Meng, Ying Zheng, Hao Liu, and Daiming Fan discusses the critical role of the tumor microenvironment (TME) in promoting multidrug resistance (MDR) in cancer cells. The TME, comprising various components such as immune cells, fibroblasts, and blood vessels, influences tumor progression, metastasis, immune escape, and drug resistance. The review highlights five key mechanisms through which the TME promotes chemoresistance: 1. **Inhibition of Immune Clearance**: The TME facilitates immune escape by modifying the immune response, allowing tumor cells to evade detection and destruction by immune cells. 2. **Soluble Paracrine Factors**: The release of soluble factors enhances tumor survival and growth by modulating angiogenesis, immune suppression, and metabolic pathways. 3. **Metabolic Reprogramming**: Hypoxic conditions in the TME lead to metabolic reprogramming, which can enhance drug resistance through mechanisms like increased expression of P-glycoprotein and altered cellular metabolism. 4. **Alteration of Peritumoral Stomatal Cells and Blood Vessels**: Changes in these structures can obstruct drug absorption and reduce therapeutic efficacy. 5. **Induction of Cancer Stem Cell Phenotype**: The TME can induce the cancer stem cell (CSC) phenotype, contributing to tumor recurrence and resistance. The review also addresses clinical strategies for targeting the TME to overcome MDR, including: - **Targeting the Immune System**: Using immune checkpoint inhibitors and combination therapies to enhance anti-tumor immune responses. - **Targeting Other TME Components**: Developing drug delivery systems and targeting specific components like fibroblasts and blood vessels to improve drug efficacy and reduce resistance. Overall, the review emphasizes the complexity of the TME and the need for a better understanding of its mechanisms to develop effective treatments for MDR cancers.