BACKGROUND: Recently, the strategy of self-assembling dendritic drug-drug conjugates into supramolecular nanoprodrug was widely explored in biomedical applications. Herein, we construct a hypoxia-responsive core-cross-linked supramolecular nanoprodrug (CSN-IR806/CB) based on a dendritic drug-drug conjugate. METHODS: We prepared a hypoxia-responsive dendritic drug-drug conjugates IR806-(Azo-CB), which was combined with β-cyclodextrin-pendant poly(ethylene glycol)-block-poly(glutamic acid) block copolymer (PEG-PGlu-CD) to construct the core-cross-linked supramolecular nanoprodrug (CSN-IR806/CB) with enhanced physiological stability through the synergy of π-π stacking interaction, host-guest complexation, hydrogen bonds, and hydrophobic interaction. RESULTS: The near-infrared (NIR) light irradiation of the CSN-IR806/CB treated tumor cells induced IR806-mediated PDT and PTT, and aggravated hypoxia, which triggered the disassembly of CSN-IR806/CB and the subsequent release of activated CB for synergetic cancer cell killing. CONCLUSIONS: The CSN-IR806/CB can realize a synergistic triple therapeutic effect of photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy (CT; i.e., PTT-PDT-CT).