Considering　that　hypoxia　is　strongly　connected　with　tumor　proliferation,　metastasis,　invasion,　and　drug　resistance,　it　is　of　significant　implication　for　alleviating　the　effects　of　hypoxia　in　tumor　treatment.　The　negligible　oxygen-dependent　nature　of　type　I　photosensitizers　(PSs)　has　made　them　appropriate　candidates　for　the　treatment　of　hypoxic　tumors.　However,　the　lack　of　effective　molecular　design　approaches,　the　phototoxicity　of　PSs　to　normal　tissue　before　and　after　treatment,　and　the　drawbacks　of　poor　hydrophilicity　severely　hinder　the　development　of　PSs　in　hypoxic　tumor　therapy.　Thus,　developing　a　hydrophilic　PS　with　good　hypoxia　resistance　and　minimal　side　effects　is　an　urgent　but　challenging　problem.　Herein,　we　present　a　nanotheranostic　(NanoPcN8O)　based　on　the　self-assembly　of　a　hydrophilic　phthalocyanine　derivative　(PcN8O),　a　hypoxia-responsive　bioreductive　phototherapeutic　agent　suitable　for　activatable　photoacoustic　(PA)　imaging　and　tumor　therapy.　Hypoxic　regions　in　various　tumors　exhibit　strong　reductive　capability,　and　only　in　such　conditions　did　NanoPcN8O　feature　multiple　N-oxide　groups　that　could　be　bioreduced　to　yield　the　product　NanoPcN8　with　abundant　electron-rich　tertiary　amine　groups,　which　switches　on　the　type　I　photodynamic　and　photothermal　effects,　facilitating　the　generation　of　type　I　reactive　oxygen　species　(ROS)　and　heat.　Better　still,　NanoPcN8O　achieved　hypoxia-induced　selective　PA　imaging　in　a　preclinical　model.　Based　on　these　merits,　the　hypoxia-induced　switchable　type　I　photodynamic　therapy　(PDT)　and　photothermal　therapy　(PTT)　strategies　demonstrated　remarkable　phototherapeutic　efficiency　with　high　biosafety.　This　delicate　design　is　anticipated　to　offer　a　novel　and　safe　strategy　to　overcome　hypoxia　resistance　in　phototherapeutics.　©　2025　The　Author(s).　Angewandte　Chemie　International　Edition　published　by　Wiley-VCH　GmbH.