Type 1 innate lymphoid cells (ILC1s) are tissue-resident cells with an enrichment in the liver. While ILC1s have been found to exert critical roles in antitumor immunity, the mechanisms regulating ILC1 functions in the tumor microenvironment are incompletely understood. Here, we found that purinergic 2X7 receptor (P2RX7) was highly expressed on ILC1s but not on conventional natural killer (cNK) cells. The P2RX7 agonist BzATP could inhibit ILC1 maintenance and effector functions via P2RX7 in vitro. Although P2rx7 deficiency alone had minor effect liver tumor progression, it enhanced ILC1 antitumor activities and inhibited tumor progression in chemotherapy-treated mice. Antagonizing P2RX7 combined with chemotherapy showed theraputic efficacy for liver cancer. Thus, our results demonstrate that P2RX7 signaling induced by chemotherapy plays a pivotal role in restraining ILC1 antitumor immunity, and antagonizing P2RX7 improves chemotherapy efficacy in combating liver cancer.