Reactive　oxygen　species　(ROS)-based　therapies,　such　as　photodynamic　therapy　(PDT)　and　chemodynamic　therapy　(CDT),　hold　great　promise　to　cancer　treatment.　However,　their　efficacies　are　subject　to　hypoxia　and　overexpressed　glutathione　(GSH)　in　tumor　microenvironment　(TME).　Herein,　we　develop　Mn　(II)　ions　and　pyropheophorbide　(PPa)　engineered　iron　oxide　nanoparticles　(IMOP)　to　regulate　tumor　hypoxia　and　deplete　GSH　for　synergistic　CDT/PDT.　In　the　TME,　IMOP　could　catalytically　decompose　hydrogen　peroxide　(H2O2)　to　hydroxyl　radicals　(·OH)　as　a　CDT　agent.　Significantly,　IMOP　exhibits　high　catalase-like　and　glutathione　peroxidase-like　activities　simultaneously.　Once　enriching　into　tumor,　IMOP　could　catalyze　H2O2　to　oxygen　(O2)　to　overcome　hypoxic　TME　for　improved　1O2　generation　via　PPa-mediated　PDT.　Meanwhile,　the　glutathione　peroxidase-like　activity　ensure　IMO　to　reduce　the　intratumoral　GSH　concentration　and　further　reduce　the　consumption　of　active　ROS　during　therapy.　We　demonstrated　that　the　regulation　by　IMOP　elicited　synergistic　CDT/PDT　efficacy　for　enhanced　ROS-based　cancer　treatment　both　in　vitro　and　in　vivo.　Moreover,　the　existence　of　Mn　(II)　allowed　IMO　with　T1　contrast　behavior　to　monitor　the　progress　of　CDT/PDT　in　magnetic　resonance　imaging.　This　work　provides　a　new　guidance　for　designing　TME-based　anticancer　platform　for　effective　and　precise　cancer　treatment.　©　2022　Elsevier　B.V.