A　major　impediment　in　photodynamic　therapy　(PDT)　against　hypoxic　tumors　is　that　the　O-2-dependent　PDT　is　seriously　limited　by　the　intrinsic　hypoxic　feature.　Hypoxia-inducible　factor-1　alpha　(HIF-1　alpha)　is　a　key　transcription　factor　in　tumor　development　and　especially　accumulates　in　hypoxic　tumors　and　has　been　recognized　as　a　novel　therapeutic　target.　Herein,　we　developed　small　molecule　HIF-1　alpha　inhibitor　Doxy　and　IR780　photosensitizer　co-incorporated　methoxy　poly(ethylene　glycol)-b-poly-(propylene　sulfide)　(mPEG(50)-b-PPS45)　nanoparticles　(NPs/ID)　as　an　ROS-responsive　theranostic　system　designed　to　enhance　PDT　efficiency　by　combining　the　benefits　of　anti-HIF-1　alpha　therapy　and　ATP　depletion.　NPs/ID　with　reinforced　phototherapy　response　in　hypoxic　tumors　displayed　enhanced　photocytotoxicity　compared　to　NPs/I　that　only　exhibited　the　PDT　effect.　On　the　other　hand,　NPs/ID　have　the　capacity　to　reduce　the　supply　of　intracellular　ATP　and　destabilize　the　intracellular　redox　homeostasis　for　enough　ROS　generation　by　suppressing　the　HIF-1　alpha　expression,　thereby　facilitating　the　therapeutic　efficiency　of　PDT.　Significantly,　NPs/ID　displayed　effective　tumor　targeting　and　NIR　imaging　ability　and　an　improved　in　vivo　efficacy　in　a　xenograft　MDA-MB-231　mouse　tumor　model　compared　with　bare　PDT.　These　findings　demonstrate　that　the　ROS-responsive　theranostic　NPs/ID　with　special　anti-HIF-1　alpha　and　ATP　depletion　behavior　represent　an　attractive　approach　for　overcoming　the　problems　of　PDT　in　hypoxic　tumors.