To　address　poor　photodynamic　efficacy　against　hypoxic　tumor　cells,　we　have　developed　a　smart　photosensitizing　agent　Ion-BDP　whose　phototherapeutic　mode　can　be　regulated　by　nitroreductase　(NTR)　that　is　rich　in　hypoxic　tumor　cells.　This　photosensitizer　(PS)　can　eliminate　outer　aerobic　tumor　cells　mainly　by　generating　reactive　oxygen　species　(ROS)　upon　illumination.　Moreover,　Ion-BDP　is　highly　sensitive　to　NTR　and　capable　of　converting　to　BDP　by　removing　the　4-nitrobenzyl　group　via　reduction　and　subsequent　self-immolation　under　hypoxic　condition.　The　formed　BDP　behaving　as　a　highly　efficient　photothermal　agent　can　further　kill　the　hypoxic　tumor　cells　by　photothermal　therapy　(PTT).　The　synergistic　antitumor　effects　of　this　PS　have　been　verified　by　in　vitro　and　in　vivo　experiments.　This　study　may　provide　a　potential　tactic　to　precisely　overcome　the　inherent　therapeutic　difficulty　arising　from　O2-distributional　heterogeneity　in　solid　tumors.　In　brief,　we　have　designed,　synthesized　and　evaluated　a　novel　NTR-regulated　PS　and　found　that　it　can　remarkably　inhibit　tumor　growth　in　both　hypoxic　and　normoxic　conditions,　which　is　proven　to　be　a　distinctive　strategy　for　maximizing　phototherapeutic　efficacy.　©　2022　Elsevier　Ltd