In this article, we explored the tumor microenvironment (TME) potential as a therapeutic target for drug development. The TME, composed of a complex network of stromal, immune, and leukemic cells, contributes significantly to disease progression and resistance to conventional therapies, including multi-drug resistance (MDR). The article discusses how interactions within the TME facilitate leukemic cell survival and proliferation, and presents emerging targeted therapies designed to disrupt these interactions. By focusing on specific components and signaling pathways in the TME, such as WNT signaling, BCR inhibitors, and immune checkpoint blockade therapies, this research aims to uncover novel treatment strategies to complement traditional anti-leukemic treatments and improve patient outcomes.