M2 macrophages secrete CCL20 to regulate iron metabolism and promote daunorubicin resistance in AML cells.

Chemotherapy resistance is a significant clinical challenge in the treatment of leukemia. M2 macrophages have been identified as key contributors to the development of chemotherapy resistance in cancer, yet the precise mechanisms by which macrophages regulate this resistance remain elusive. Our study has identified CCL20 as a pivotal factor in the promotion of chemoresistance in AML cells by M2 macrophages. The chemotherapeutic agent daunorubicin induces a marked increase in ROS and lipid peroxidation levels within AML cells. This is accompanied by the inhibition of the SLC7A11/GCL/GPX4 signaling axis, elevated levels of intracellular free iron, disrupted iron metabolism, and consequent mitochondrial damage, ultimately leading to ferroptosis. Notably, CCL20 enhances the ability of AML cells to maintain iron homeostasis by upregulating SLC7A11 protein activity, mitigating mitochondrial damage, and inhibiting ferroptosis, thereby contributing to chemotherapy resistance. Furthermore, in vivo experiments demonstrated that blocking CCL20 effectively restores the sensitivity of AML cells to daunorubicin chemotherapy. Collectively, these findings underscore the complex interplay between M2 macrophages, CCL20 signaling, and chemotherapy resistance in AML, highlighting potential therapeutic avenues for intervention.