Targeted　delivery　of　radiosensitizers　and　real-time　monitoring　of　hypoxia　are　crucial　for　overcoming　radiotherapy　resistance　in　hypoxic　tumors.　Here,　we　report　A-Cy-Ni-RGD,　a　triple-targeted　nitroimidazole　(Ni)-linked　radiosensitizer　that　self-assembles　into　nanoparticles　(A-Cy-Ni-RGD　NPs)　for　bimodal　near-infrared　fluorescence　(NIR　FL)　and　photoacoustic　(PA)　imaging-guided　radio-immunotherapy.　A-Cy-Ni-RGD　NPs　specifically　accumulate　in　αvβ3-positive　tumors,　where　they　are　hydrolyzed　by　carboxylesterase　to　form　Cy-Ni-RGD　NPs,　with　enhanced　FL　at　710　nm　and　dual　PA　signals　at　680　and　730　nm.　Under　hypoxic　conditions,　nitroreductase　(NTR)　further　reduces　these　NPs,　covalently　labeling　endogenous　proteins　and　increasing　NP　size.　This　process　partially　alleviates　aggregation-caused　quenching　effect,　increasing　the　FL710　signal　and　decreasing　the　PA730　signal,　enabling　real-time　tracking　of　tumor-specific　delivery　and　hypoxia.　Following　low-dose　X-ray　irradiation　(2　Gy),　elevated　NTR　expression　promotes　further　Cy-Ni-RGD　NPs　reduction,　enhancing　proteins　labeling　and　causing　DNA　damage.　Moreover,　radiosensitization　with　A-Cy-Ni-RGD　NPs　triggers　robust　immunogenic　cell　death,　stimulating　antitumor　immunity　that　inhibits　tumor　growth　and　metastasis,　significantly　prolonging　survival　in　mice　with　orthotopic　4T1　tumors.　This　work　underscores　the　potential　of　self-assembling,　triple-targeted　radiotheranostic　agents　for　improving　tumor　targeting,　imaging,　and　radiotherapy　efficacy　in　hypoxic　tumors.　©　2025　Wiley-VCH　GmbH.