AMD1-driven MTA production sustains chemoresistance by rewiring PMN-MDSC immunosuppression

Chemoresistance reflects both tumor cell-intrinsic adaptation and remodeling of the immune microenvironment. However, the mechanisms by which chemoresistant tumor cells orchestrate and sustain an immunosuppressive microenvironment remain poorly understood. Here, we demonstrate that chemoresistant tumors exhibit marked accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which exert potent immunosuppressive effects on CD8+T cells and are critical for drug resistance. Metabolomic profiling reveals that resistant tumor cells release the metabolite 5'-methylthioadenosine (MTA). MTA enhances the immunosuppressive function of PMN-MDSCs by bolstering JAK-STAT3 signaling. Mechanistically, MTA binds to the protein tyrosine phosphatase PTPN2 to block its phosphatase activity, thereby potentiating activation of JAK-STAT3 signaling pathway. Moreover, we uncover that adenosylmethionine decarboxylase 1 (AMD1) is the key metabolic determinant of MTA accumulation in chemoresistant tumor cells. Genetic or pharmacological AMD1 inhibition significantly decreases MTA level, diminishes PMN-MDSC immunosuppressive function, and re-sensitizes the resistant tumors to chemotherapy and immunotherapy. Our findings identify MTA as an important metabolic link between chemoresistant tumor cells and PMN-MDSCs to sustain immunosuppression and therapeutic resistance. Targeting AMD1-dependent MTA production represents a valuable strategy for overcoming chemo-immunotherapy resistance.