Despite new biological insights and recent therapeutic advances, many tumors remain at baseline during treatments. Therefore, there is an urgent need to find new therapeutic strategies to improve the care of patients with solid tumors. P2RX7 receptor (P2XR7), an ATP-gated ion channel characterized by its ability to form large pore within the cell membrane, is described by most of the investigators as a “chef d’orchestre” of the antitumor immune response. The purpose of this review is to detail the recent information concerning different cellular mechanisms linking P2RX7 to hallmarks of cancer and to discuss different progresses in elucidating how activation of the ATP/P2RX7/NLRP3/IL-18 pathway is a very promising approach to fight cancer progression by increasing antitumor immune responses.