Targeting tumor-infiltrating regulatory T (TI-T-reg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97-Npl4 complex has a critical function in TI-T-reg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral T-reg cell homeostasis. The p97-Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-T-reg cell development. Collectively, this work shows an important role for the p97-Npl4 complex in controlling T-reg-T(H)17 cell balance in tumors and identifies possible targets for immunotherapy.