The tumor hypoxic microenvironment is a dynamic status that is closely related to tumor growth, metastasis, clearance, and recurrence. Hypoxic conditions are present in almost all tumors, which greatly reduce the clinical effects of tumor therapy. Considering the physical tolerance and dose-related side effects of clinical cancer radiotherapy (RT) patients, herein, a universal two-step strategy is designed based on safe, noninvasive, deep penetration, and intensity-controlled ultrasound method to alleviate hypoxia and enhance tumor RT. The first step is to alleviate the tumor hypoxia by physical stimulation from noninvasive and controllable low-intensity pulsed ultrasound (LIPUS). In the second step, based on the use of polyethylene glycol (PEG) polymer, PEG-polyphenols are applied to encapsulate radiosensitizers platinum (Pt) and assembled with sonosensitizers PEG-purpurin 18 (PEG-P18) into nanoparticles (NPs) as PP18-Pt NPs with good biocompatibility and pharmacokinetic properties in combination with RT and sonodynamic therapy to achieve a high level of reactive oxygen species-mediated tumor oxidative stress. The results show that LIPUS is a safe modality to effectively modulate hypoxia levels. The two-step strategy based on PP18-Pt NPs can effectively inhibit the growth of breast cancer tumors and activate the body's antitumor immune response.