The abundant intracellular glutathione (GSH) in cancer cells severely undermines the therapeutic efficacy of different treatments due to their role in protecting cancer cells from the associated oxidative stress. Developing a highly integrated system to consume GSH would help to improve the therapeutic outcomes. In this study, supramolecular prodrug self-assemblies (SPSAs) with IR825 loaded inside were developed to consume GSH via two-pronged pathways while augmenting the therapeutic potency of chemo/photothermal treatment. SPSAs were prepared using water-soluble pillar[6]arene (WP[6]) as host units and H₂O₂-responsive nitrogen mustard prodrug, chlorambucil-(phenylboronic acid pinacol ester) conjugates (Cb-BE), as the guests. When SPSAs were internalized by cancer cells, the generation of quinone methide (QM) from Cb-BE and singlet oxygen (¹O₂) from irradiation-activated IR825 could consume GSH in a concerted way. As such, the therapeutic efficacies of the released chlorambucil and the accompanied hyperthermia were augmented toward synergistically inhibiting tumor growth.