Fig. 3

The mechanisms of action of targeting CD39 in cancer. CD39 blocking antibody can increase the level of extracellular ATP (eATP) in the tumor microenvironment (TME) by inhibiting ATP degradation by CD39. The increased eATP levels activate the P2 × 7 receptor on macrophages and dendritic cells (DCs), resulting in inflammasome-mediated release of pro-inflammatory cytokines, including IL-18 and IL-1β, which support effector T cell and natural killer (NK) cell-mediated cytotoxicity. The increased eATP levels not only induce pyroptosis in P2 × 7 + macrophages (A) but also bind to P2 × 7 on DCs, enhancing antigen presentation and maturation, further supporting effector T cell and NK cell-mediated cytotoxicity (B). These are the two known mechanisms of action of targeting CD39 in cancer. Additionally, targeting CD39 may downregulate CD39 expression by binding to the CD39 receptor (C) and directly activate CD39 + tumor-specific T cells or CD39 + NK cells (D), which could be two potential new mechanisms