Numerous nanoparticles have been utilized to deliver Fe2+ for tumor ferroptosis therapy, which can be readily converted to Fe3+via Fenton reactions to generate hydroxyl radical (•OH). However, the ferroptosis therapeutic efficacy of large tumors is limited due to the slow conversion of Fe3+ to Fe2+via Fenton reactions. Herein, a strategy of intratumor Fe3+/2+ cyclic catalysis is proposed for ferroptosis therapy of large tumors, which was realized based on our newly developed hollow mesoporous iron sesquioxide nanoparticle (HMISN). Cisplatin (CDDP) and Gd-poly(acrylic acid) macrochelates (GP) were loaded into the hollow core of HMISN, whose surface was modified by laccase (LAC). Fe3+, CDDP, GP, and LAC can be gradually released from CDDP@GP@HMISN@LAC in the acidic tumor microenvironment. The intratumor O2 can be catalyzed into superoxide anion (O2•-) by LAC, and the intratumor NADPH oxidases can be activated by CDDP to generate O2•-. The O2•- can react with Fe3+ to generate Fe2+, and raise H2O2 level via the superoxide dismutase. The generated Fe2+ and H2O2 can be fast converted into Fe3+ and •OH via Fenton reactions. The cyclic catalysis of intratumor Fe3+/2+ initiated by CDDP@GP@HMISN@LAC can be used for ferroptosis therapy of large tumors.