We show that treatment of prostate cancer cells with potent, specific ATR inhibitors (ATRi) leads to robust activation of the cGAS-STING signaling pathway, growth inhibition, and cell death. We also demonstrate that ATRis repress ATR-Chk1 replication stress signaling, which results in activation of a CDK1-SPOP axis, PD-L1 degradation, and derepression of a cGAS-STING-IFN-ß-IFNAR1-driven, autocrine, cytotoxic signaling pathway. ATRi and anti-PD-L1 combination treatment resulted in synergistic, anti-tumor activity in a syngeneic mouse androgen-indifferent, aggressive prostate cancer model. scRNA-seq analysis of tumor tissue samples from this model demonstrated increased activation of cGAS-STING, IFN-ß, and apoptotic signaling in combination versus ATRi single agent treatment. Our findings provide a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade, leading to the development of active early-phase clinical trials and reveal mechanismbased opportunities for improving outcomes for men with advanced prostate cancer by combining immunotherapy and agents that induce mitotic catastrophe.

Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived foam cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in foam cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis.

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Radiotherapy with or without concurrent chemotherapy is the standard treatment for nasopharyngeal carcinoma (NPC) patients, whose efficacy is limited partly by intrinsic and acquired radioresistance. DNA methyltransferase 3B (DNMT3B) has been reported to participate in tumorigenesis via DNA methylation, but its role in mediating progression and radioresistance of NPC remains unclear. Therefore, we conducted the following studies to explore the relationship between DNMT3B and NPC. Here, we found that DNMT3B was elevated in NPC tissues and predicted the poor prognosis of NPC patients. We demonstrated for the first time that ionizing radiation could induce DNMT3B, which might be one of the reasons for radioresistance. Silencing of DNMT3B inhibited migration and invasion via suppressing epithelialmesenchymal transition (EMT) in NPC cells. Furthermore, silencing DNMT3B restored and activated p53 and p21 via DNA demethylation, which led to cell cycle arrest and apoptosis, resulting in increased radiosensitivity of NPC both in vitro and in vivo. DNMT3B functions as a novel oncogene in the radioresistance of NPC through regulating EMT, cell cycle, and apoptosis. Therefore, DNMT3B could be a potential target for NPC treatment.