Perylene diimide (PDI) radical anions have attracted increasing attention as hypoxia-responsive photothermal agents due to their strong near-infrared (NIR) absorption and efficient photothermal conversion. However, their biomedical application is often limited by aggregation-induced quenching and poor structural tunability. In this work, we report a rationally engineered four-arm PDI derivative (PDI-4Alky·4Cl) bearing terminal alkyne groups, which not only suppresses π–π stacking via steric and electrostatic repulsion, but also serves as a versatile molecular scaffold for further functionalization. The resulting PEGylated product (PDI-2PEG) exhibits excellent aqueous stability, high radical yield, and strong NIR photothermal performance (conversion efficiency up to 51.6%). Importantly, PDI-2PEG demonstrates hypoxia-triggered radical generation and tumor-specific photothermal ablation in vivo. This study highlights a structurally modular PDI platform that integrates radical-based photothermal therapy with synthetic flexibility, offering a promising strategy for the development of next-generation tumor-selective theranostic agents.