Fig. 1: Schematic illustration of the preparation procedure of SHC4H and the anti-tumor mechanism under hypoxia.

a The conjugation of HSA with free thiol groups to methacrylamide-monomodification sulfonate modified azocalix[4]arene (MAM-SAC4A) through a photoclick chemistry reaction. SHC4H was constructed by self-assembly process after encapsulating SMNB and HCQ. b i-ii. Hypoxia-responsive drug release and fluorescence imaging capabilities of SHC4H. Before laser irradiation, HCQ alkalized lysosomes to block hypoxia-induced pro-survival mitophagy, resulting in an imbalance and increased oxidative stress. iii. Upon laser irradiation, SMNB underwent O2•--mediated type I M-PDT, and the continuous accumulation of mitophagy flux further induced an intracellular ROS storm and amplified oxidative stress. The ROS storm within the mitochondria led to two distinct modes of cell death in different tumor cells.