Photothermal therapy/photodynamic therapy (PTT/PDT), as a noninvasive therapeutic modality, has been extensively applied in superficial tumor treatment. However, their curative effects were largely weakened due to hypoxia and an elevated glutathione (GSH) microenvironment. Herein, zinc phthalocyanine (ZnPc) and sulfasalazine (SAS) coloaded nanoaggregates (Z-S@B NAs) with Prussian blue (PB) functionalization (PB/Z-S@B NAs) were fabricated via self-assembly and using an in situ oxidative polymerization method for tumor PTT/PDT sensitization. The designed PB/Z-S@B NAs were capable of triggering local hyperthermia and generating substantial reactive oxygen species (ROS) under 660- and 808-nm laser irradiation. Notably, the PB/Z-S@B NAs exhibited favorable catalase-like (CAT-like) activity that decomposed hydrogen peroxide into oxygen, which further enhanced tumor cell sensitivity to PTT/PDT. Moreover, SAS from the PB/Z-S@B NAs remarkably decreased the antioxidant GSH level, resulting in a synergetic tumor-killing effect. Collectively, this study provides a versatile nanoplatform to overcome intrinsic antitumor effect and enhance tumor sensitivity to PTT/PDT.