While in this study, we reveal a novel mechanism of CD39-mediated tumor immune escape, that is, tumor exosome-transferred CD39 protein significantly reduces the intracellular ATP level and increased the ratios of AMP/ATP, which subsequently modulated the metabolic AMPK/mTOR balance in CD4+ T cells, ultimately promoting Treg cells and suppressing Teff cells. Here, ENTPD1 is linked to neoplasm.