The emerging aggregation-induced emission luminogens (AIEgens) with high QY, good photostability and efficient ROS generation in the aggregated state are ideal candidates to construct chemo/bioprobes. While, AIEgens emitting bright fluorescence upon aggregation can cause large background noise during bio-imaging. To fulfill the whole potential of AIE photosensitizers and smartly tune their photophysical properties, a noncovalent strategy based on the host-guest interaction is proposed. In contrast to single molecule systems, supramolecular interactions can be facilely operated and extensively used for high throughput screening. Organic macrocycles as the main host compounds are essential ingredients in supramolecular assembly, which can selectively include guest molecules in their inherent cavities to form complexes. Among them, calixarene affording a cone conformation is well-known for easy alteration, good compatibility, and multiple responses to stimuli. Now, calixarene derivatives have been widely utilized for biomedical materials in bio-imaging, drug delivery, and therapeutic agents. For example, Guo reported several calixarene-based supramolecular fluorescence probes for hypoxia imaging but without deeply exploring their antitumor capability. Herein, we develop a supramolecular assembly strategy based on sulfonate-functionalized azocalix [4]arene (SAC4A) and red-emitting AIEgen for hypoxia-responsive bioimaging and photodynamic therapy. In this system, cationic AIEgen composed of triphenylamine and quaternary ammonium salt (namely TPA-H) can be encapsulated in the cavity of azocalix [4]arene through electrostatic interaction (Scheme 1A). The as-prepared supramolecular complexes result in a quenched fluorescence. When exposing the complexes under hypoxia, the azo group is reduced to aniline derivative and released the included AIEgen, recovering its pristine fluorescence for cell imaging. Interestingly, the dissociative TPA-H undergoes cell membrane-to-mitochondria translocation during fluorescence imaging, constructing a realtime self-reporting system to monitor the PDT process in situ (Scheme 1B). Moreover, TPA-H can generate efficient singlet oxygen ( 1 O2) and superoxide radical anions (O2 •-) under light excitation for PDT with good performance. In vivo hypoxiaresponsive tumor imaging and therapy manifest that our supramolecular complexes have good biosafety and efficient antitumor efficacy. It is predicted that such host-guest strategy avoids complicated molecular synthesis and paves a way for efficient image-guided PDT.