Triple-negative breast most cancers (TNBC) is a extremely heterogeneous and malignant tumor with a excessive danger of recurrence and metastasis [1], [2]. One of the crucial efficient methods of combating tumor recurrence and metastasis is by using the host’s immune system [3], [4]. Sadly, the response fee of tumor immunotherapy is weak underneath the affect of the advanced tumor immune microenvironment usually [5], [6]. Consequently, new methods to fight TNBC urgently must be developed. A latest discovery of a novel inflammatory cell demise mode often called pyroptosis is quicker than apoptosis [7], [8]. Pyroptosis characteristically triggers the discharge of tumor-associated antigens and a substantial quantity of pro-inflammatory elements, which activate the immune system. The induction of pyroptosis in tumor cells can successfully inhibit tumor recurrence and metastasis [9], [10]. Conventional strategies to induce pyroptosis in tumor cells have excessive unintended effects and low induction charges. The rise of reactive oxygen species (ROS) could cause the lower of mitochondrial transmembrane potential, promote the discharge of cytochrome C, after which activate the caspase enzyme to induce cell apoptosis. Thus, switching from ROS-mediated apoptosis to pyroptosis successfully overcomes these shortcomings [11], [12]. From this level, radiotherapy (RT) might have nice potential to induce pyroptosis by radiation-induced ROS storms in tumors. RT, which makes use of high-energy radiation to kill tumor cells, is essentially the most outstanding scientific tumor therapy methodology because of its deep tissue penetration and good spatiotemporal selectivity [13], [14]. Furthermore, the event of nano-radiosensitizers that include high-Z components has enabled improve the era of a lot of ROS by radiation hydrolysis [15], [16], [17], [18]. Among the many nano-radiosensitizers, hafnium oxide nanoparticles (HfO2 NPs) are the primary inorganic nano-radiosensitizers to go to the clinic because of their excessive biocompatibility and X-ray absorption capability [19], [20].
Research have revealed that ROS can activate Caspase-3, which cleaves Gasdermin E (GSDME) protein in its energetic state, releasing the N-terminal area that causes cell swelling and rupture by perforating the cell membrane when GSDME expression is excessive [21], [22]. In distinction, apoptosis is initiated when GSDME expression is low. Thus, the Caspase-3/GSDME signaling pathway acts as a change that regulates the stability between apoptosis and pyroptosis of tumor cells, providing a novel method for the transition from apoptosis to pyroptosis [23], [24]. Sadly, GSDME is especially expressed at excessive ranges in regular tissues, whereas in some tumor tissues, it undergoes transcriptional inhibition because of hypermethylation of the GSDME gene promoter area [25], [26], [27], [28]. Decitabine (DAC), a DNA methylase inhibitor that hinders DNA methyltransferases’ exercise, has been accredited by the FDA for treating myelodysplastic syndromes [29], [30]. This means that DAC can activate GSDME gene expression and convert radiation-induced apoptosis to pyroptosis. Nevertheless, it’s ineffective in stable tumor tissue, and the really helpful doses might trigger antagonistic reactions resembling myelosuppression [31], [32]. Subsequently, exact supply and extra focus of DAC to tumor tissues utilizing nano-radiosensitizers can reverse the GSDME expression, convert ROS-mediated apoptosis to pyroptosis, activate anti-tumor immunity, and increase the efficacy of treating tumors.
To deal with the problems talked about above, we developed composite nano-radiosensitizers, DAC@O-HONs, consisting of ultra-small HfO2 and DAC, as a possible methodology for inducing radiotherapy-induced pyroptosis of tumor cells (Scheme 1). Analyzing The Most cancers Genome Atlas (TCGA) database, we discovered that the GSDME expression is decreased in breast most cancers in comparison with paracancerous tissues. Thus, upregulating GSDME expression is essential in transitioning radiation-induced breast most cancers cell apoptosis to pyroptosis. The O-HONs nano-radiosensitizer generates a major quantity of ROS underneath irradiation, inducing tumor cell apoptosis. The epigenetic drug DAC will increase GSDME expression, thereby selling tumor cell pyroptosis. Moreover, pyroptosis releases tumor-associated antigens and inflammatory elements, activating the host’s anti-tumor immunity and stopping tumor recurrence and metastasis. In abstract, we suggest a novel strategy to treating malignant tumors by combining nano-radiosensitizers and DNA methylation inhibitors, offering a extremely efficient tumor therapy technique.