Photodynamic　therapy　(PDT)　has　arisen　as　a　promising　method　due　to　its　spatiotemporal　precision　and　minimal　invasiveness.　It　encounters　significant　obstacles　in　solid　tumors　due　to　hypoxia-induced　therapeutic　resistance　and　the　self-protective　mechanisms　of　cancer　cells　facilitated　by　MutT　homolog　1　(MTH1),　an　enzyme　involved　in　oxidative　damage　repair.　Herein,　we　fabricate　a　tumor-microenvironment　responsive　CRISPR　nanoplatform　based　on　hollow　mesoporous　manganese　dioxide　(H-MnO2)　for　PDT.　This　platform　utilizes　H-MnO2　to　produce　oxygen　(O2)　through　the　decomposition　of　hydrogen　peroxide　(H2O2)　in　TME,　thereby　mitigating　hypoxia　and　enhancing　reactive　oxygen　species　(ROS)　generation.　The　high　concentration　of　glutathione　(GSH)　and　hyaluronidase　(HAase)　in　TME　induces　the　release　of　CRISPR/Cas9　ribonucleoproteins　(RNP)　to　target　the　MTH1　gene,　thereby　impairs　oxidative　damage　repair　pathways　and　amplifys　ROS-mediated　cytotoxicity.　The　released　Mn2+　ions　function　as　immunomodulatory　agents,　activate　innate　immune　responses　via　stimulating　STING　signal　pathway.　In　vitro,　IHMRH　NPs　markedly　increased　intracellular　O2　levels,　ROS　production,　lipid　peroxidation　and　DNA　damage,　leading　to　tumor　cell　death,　immune　activation,　and　effective　gene　editing.　In　vivo,　the　nanoplatform　suppressed　tumor　growth,　diminished　MTH1　gene　expression,　stimulated　dendritic　cell　(DC)　maturation　through　immunogenic　cell　death　(ICD).　This　multimodal　nanosystem　may　amplifies　oxidative　stress,　collaborates　with　innate　and　adaptive　immune　activation　to　surpass　the　constraints　of　traditional　PDT.　The　research　presents　a　novel　framework　for　cancer　combination　therapy　by　systematically　integrating　nanotechnology　with　precision　gene　editing.　©　2025　Elsevier　Inc.