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Hypoxia in the tumor microenvironment (TME) greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy (SDT); this phenomenon is further exacerbated by increased glutathione (GSH) levels in cancer cells. Simultaneously, cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation but the efficacy of glucose oxidase (GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor. Glucuronide 3-phosphate dehydrogenase (GADPH) is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement. Here, we innovatively proposed thiol–ene click reactions based on a two-dimensional metal–organic framework (MOF) modification for tumor treatments to enable the combination of SDT and starvation therapy. Experimental studies demonstrated that the prepared material could consume GSH and GADPH free from oxygen in TME, which benefited from the thiol–ene click reactions between the MOF and thiol substances in cancer cells. Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently. This study is expected to create a promising avenue for thiol–ene click reactions in SDT therapy and cancer starvation therapy for cancer.