Hypoxia-activated　prodrugs　(HAPs)　have　drawn　increasing　attention　for　improving　the　antitumor　effects　while　minimizing　side　effects.　However,　the　heterogeneous　distribution　of　the　hypoxic　region　in　tumors　severely　impedes　the　curative　effect　of　HAPs.　Additionally,　most　HAPs　are　not　amenable　to　optical　imaging,　and　it　is　difficult　to　precisely　trace　them　in　tissues.　Herein,　we　carefully　designed　and　synthesized　a　multifunctional　therapeutic　BAC　prodrug　by　connecting　the　chemotherapeutic　drug　camptothecin　(CPT)　and　the　fluorescent　photothermal　agent　boron　dipyrromethene　(BODIPY)　via　hypoxia-responsive　azobenzene　linkers.　To　enhance　the　solubility　and　tumor　accumulation,　the　prepared　BAC　was　further　encapsulated　into　a　human　serum　albumin　(HSA)-based　drug　delivery　system　to　form　HSA@BAC　nanoparticles.　Since　the　CPT　was　caged　by　a　BODIPY-based　molecule　at　the　active　site,　the　BAC　exhibited　excellent　biosafety.　Importantly,　the　activated　CPT　could　be　quickly　released　from　BAC　and　could　perform　chemotherapy　in　hypoxic　cancer　cells,　which　was　ascribed　to　the　cleavage　of　the　azobenzene　linker　by　overexpressed　azoreductase.　After　irradiation　with　a　730　nm　laser,　HSA@BAC　can　efficiently　generate　hyperthermia　to　achieve　irreversible　cancer　cell　death　by　oxygen-independent　photothermal　therapy.　Under　fluorescence　imaging-guided　local　irradiation,　both　in　vitro　and　in　vivo　studies　demonstrated　that　HSA@BAC　exhibited　superior　antitumor　effects　with　minimal　side　effects.　©　2022　American　Chemical　Society.　All　rights　reserved.