In summary, a hypoxia-responsive supramolecular photodynamic therapy system was constructed based on a cationic AIEgen (TPA-H) and water-soluble azocalixarene (SAC4A). Upon supramolecular assembly of TPA-H and SAC4A through electrostatic interaction, the red fluorescence of TPA-H was quenched and its ROS generation was largely inhibited. In hypoxic tumors, the azo group of SAC4A can be reduced to aniline derivative and released the included TPA-H to recover pristine fluorescence and ROS. Cell imaging revealed that free TPA-H translocated from cell membrane to mitochondria, achieving dual-organelle targeting and a realtime self-reporting system to monitor dynamic molecule migration in situ. In vivo hypoxia-responsive tumor imaging and therapy were performed to find this supramolecular complexes have good biosafety and efficient antitumor activity. This work presented a promising platform for the construction of hypoxia-responsive supramolecular photosensitizer system and it will enrich the biomedical study based on supramolecular strategy.