Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

Although p53-mediated cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, emerging evidence suggests that the metabolic activities of p53 are also important. Here we show that p53 inhibits cystine uptake and sensitizes cells to ferroptosis, a non-apoptotic form of cell death, by repressing expression of SLC7A11, a key component of the cystine/glutamate antiporter. Notably, p53(3KR), an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, fully retains the ability to regulate SLC7A11 expression and induce ferroptosis upon reactive oxygen species (ROS)-induced stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. Moreover, SLC7A11 is highly expressed in human tumours, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53(3KR)-mediated tumour growth suppression in xenograft models. Our findings uncover a new mode of tumour suppression based on p53 regulation of cystine metabolism, ROS responses and ferroptosis.

Tailored to the specific tumour microenvironment, which involves acidity and the overproduction of hydrogen peroxide, advanced nanotechnology has been introduced to generate the hydroxyl radical (. OH) primarily for tumour chemodynamic therapy (CDT) through the Fenton and Fenton-like reactions. Numerous studies have investigated the enhancement of CDT efficiency, primarily the increase in the amount of . OH generated. Notably, various strategies based on the Fenton reaction have been employed to enhance . OH generation, including nanomaterials selection, modulation of the reaction environment, and external energy fields stimulation, which are discussed systematically in this Minireview. Furthermore, the potential challenges and the methods used to facilitate CDT effectiveness are also presented to support this cutting-edge research area.

Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.