Synergistic therapies, such as chemo-photodynamic therapy, have been growing fast because of their efficacy against cancers. Although metal-organic frameworks have been widely studied in the field of drug delivery, the metal-organic frameworks (MOFs) with a two-dimensional (2D) structure integrated by photosensitizers are rarely reported. However, chemo-photodynamic therapy still has limitations such as the inhibitory effect from intracellular glutathione (GSH). In this work, a simple bottom-up synthesis method was used to synthesize a pH-responsive drug delivery system with a 2D MOF structure. In particular, tetracarboxyporphyrin (TCPP) derivatives were coordinated with bivalent copper ions as organic bridging molecules in a polyvinylpyrrolidone (PVP) solution, and copper porphyrin MOFs (Cu-TCPP nanosheets) were synthesized by a hydrothermal method from bottom to top. DOX was loaded onto Cu-TCPP nanosheets by π-π stacking with a high drug loading rate of 33%. DOX@Cu-TCPP nanosheets showed pH-responsive DOX releasing behaviour and significant GSH scavenging ability. In addition, the evaluation of in vitro and in vivo treatment showed that DOX@Cu-TCPP nanosheets had high anti-tumor activity and excellent biocompatibility. Therefore, this study opens a new idea for the application of MOF nanosheets in tumor therapy and provides a supporting basis for the treatment of cancers by chemo-photodynamic synergistic therapy.