Photodynamic　therapy　(PDT)　has　been　showing　great　potential　in　cancer　treatment.　However,　the　efficacy　of　PDT　is　always　limited　by　the　intrinsic　hypoxic　tumor　microenvironment　(TME)　and　the　low　accumulation　efficiency　of　photosensitizers　in　tumors.　To　address　the　issue,　a　multifunctional　hollow　multilayer　nanoplatform　(H-MnO2@TPyP@Bro) comprising　manganese　dioxide,　porphyrin　(TPyP)　and　bromelain　(Bro),　is　developed　for　enhanced　photodynamic　therapy.　MnO2　catalyzes　the　intracellular　hydrogen　peroxide　(H2O2)　to　produce　oxygen　(O2),　reversing　the　hypoxic　TME　in　vivo.　The　generated　O2　is　converted　into　singlet　oxygen　(1O2)　by　the　TPyP　shell　under　near-infrared　light,　which　can　inhibit　tumor　proliferation.　Meanwhile,　the　Bro　can　digest　collagen　in　the　extracellular　matrix　around　the　tumor,　and　can　promote　the　accumulation　of　H-MnO2@TPyP@Bro　in　the　deeper　tumor　tissue,　further　improving　the　therapeutic　effect　of　PDT.　In　addition,　MnO2　can　react　with　the　overexpressed　glutathione　in　TME　to　release　Mn2+.　Consequently,　Mn2+　not　only　induces　chemo-dynamic　therapy　based　on　Fenton　reaction　by　converting　H2O2　into　hydroxyl　radicals,　but　also　activates　the　Mn2+-based　magnetic　resonance　imaging.　Therefore,　the　developed　H-MnO2@TPyP@Bro　nanoplatform　can　effectively　modulate　the　unfavorable　TME　and　overcome　the　limitations　of　conventional　PDT　for　cancer　diagnostic　and　therapeutic.　©　2022　Wiley-VCH　GmbH.