UC Davis

Methylthioadenosine phosphorylase (MTAP) is an enzyme involved in the polyamine biosynthesis pathway, catalyzing the phosphorylation of methylthioadenosine (MTA) for the regeneration of methionine and adenine. Notably, MTAP has been found frequently deleted in many cancers, which was associated with a worse prognosis. This study demonstrated MTAP regulated tumor-intrinsic immune-related pathways including PI3K/AKT, MEK/ERK, and JAK/STAT. MTAP-deficient tumor cells exerted immunosuppression and evasion by elevating pro-tumoral cytokines, programmed death-ligand 1 (PD-L1), and the tolerance of immune cell-mediated killing. The results from humanize mice indicated that MTAP-deficiency mediated immune dysfunction and attenuated immune responses. Furthermore, from CyTOF analysis, MTAP deficiency reshaped immune cell responses to tumor cells and impaired intratumoral immunity to support tumorigenesis in vitro and in vivo. These results indicate that MTAP deletion reconstructs the tumor microenvironment via cytokine reprogramming and restructuring of immune infiltrates thereby promoting cancer malignancy.