This study aims to develop a pH-responsive nanosuspension for localized cancer therapy by integrating photothermal therapy (PTT) and chemodynamic therapy (CDT). Initially, we synthesized a compound containing two five-membered cyclic orthoester bonds (OE) as a liquid pharmaceutical excipient. This OE was subsequently coloaded with the photothermal agent indocyanine green (ICG) and iron oxide nanoparticles (FeO), forming a stable nanosuspension (OE/ICG/FeO). OE exhibits acid-sensitive degradation, enabling controlled drug release in the tumor microenvironment. The FeO nanoparticles can induce the generation of reactive oxygen species (ROS) through the Fenton reaction, which synergizes effectively with the photothermal effect of ICG. Additionally, the OE/ICG/FeO formulation prolongs drug retention in tumor tissues and enhances drug penetration. Furthermore, the formulation induces immune modulation via FeO, thereby enhancing the overall therapeutic efficacy. Under 808 nm near-infrared laser irradiation, a tumor suppression rate of 84.6% was achieved through the combination of photothermal and chemodynamic therapies and immunotherapy. This study highlights the potential of OE-based nanosuspensions for localized cancer treatment, offering a multifunctional strategy to improve treatment outcomes while minimizing systemic toxicity.