1. Role of Pyroptosis in the Initiation and Progression of Cervical Cancer
1.1. Human Papillomavirus (HPV) Inhibits Pyroptosis of Infected Cells
Human papillomavirus (HPV) infection is the major cause of cervical cancer. HPV evades host antiviral immunity through viral genome integration, which can transform infected cervical cells into cancer cells. Some studies have demonstrated that HPV can inhibit the activation of the host adaptive immune gene network that encodes anti-pathogen molecules, chemotaxis and pro-inflammatory factors and proteins involved in antigen presentation. Of which, IL-1β is a key effector molecule in initiating host innate immune response and has a strong immune stimulatory activity. Abnormal release or loss of expression of IL-1β will lead to changes in the local pathological microenvironment of inflammation, which will lead to the loss of normal immune surveillance 
. As an important secretory factor of pyroptosis, IL-1β is tightly regulated in an inflammatory body/caspase-1-dependent manner at both transcriptional and post-translational levels 
. Inflammatory bodies usually induce anti-tumor immune response in two ways. One is releasing pro-inflammatory factors through a caspase-1-dependent manner in immunoreactive cells. The other is that NLRP3 inflammatory bodies are activated by ATP to release tumor suppressor factor IL-1β, inducing pyroptosis, thereby removing malignant tumor precursor cells and achieving the effect of anti-tumorigenesis 
. Therefore, pyroptosis plays an anti-tumor role in the process of tumor formation, while HPV inhibits the progression of pyroptosis by suppressing the expression of IL-1β, IL-18 and inflammasomes, thus promoting tumor progression. It was found that sirtuin 1 (SIRT 1) was over-expressed in HPV-infected cervical cancer cells, and that this increased SIRT 1 inhibits the expression of the AIM 2 inflammasome, hereby suppressing pyroptosis and promoting proliferation of the cancer cells 
. The HPV E7 protein can inhibit cell pyrogenesis induced by dsDNA transfection. The recruitment of E3 ubiquitin ligase TRIM21 by HPV E7 causes ubiquitination and degradation of IFI16 inflammatory bodies, leading to inhibition of cell pyroptosis and immune surveillance 
. HPV16 E6 was reversely correlated with the expression of IL-18 
. E6 could bind to IL-18 and promote degradation of IL-18 by an ubiquitination pathway, thereby interfering with the local inflammatory process caused by the cascade of downstream effects of IL-18 
. Moreover, Matamoros et al. found that local expression of IL-1β and IL-18 was significantly reduced in cervical tissues of patients with cancer compared to that in samples from normal control group, demonstrating that an increase in the risk of progression of pre-neoplastic lesions to cancer was found to be 2.5 and 2.08 times higher in women with lower IL-1β and IL-18 expression, respectively 
. These findings not only reveal an important immune escape mechanism during HPV infection, but also provide a novel potential target for the antiviral and anti-tumor therapies.
1.2. Role of Pyroptosis in the Initiation and Progression of Cervical Cancer: Suppressor or Promotor?
Different pathways of pyroptosis play a role in the occurrence and progression of cervical cancer. NLRP3, the most documented inflammasome, is an inflammasome that exists widely in tumor cells and its expression is regulated by the NF-κB pathway 
. NLRP3 is also widely expressed in a variety of inflammatory cells, skin keratinocytes and epithelial cells. Current studies demonstrate that the activation of NLRP3 includes a semi-ion channel model, ROS model and a lysosomal rupture model. The ROS model is mainly used to activate the NLRP3 inflammasome to induce pyroptosis of cervical cancer cells 
. Abdul-Sater et al. infected HeLa cells with Chlamydia trachomatis to stimulate the expression of an inflammasome 
. They found that Chlamydia trachomatis infection led to the outflow of potassium ions from HeLa cells through its specific potassium channels, thereby stimulating the increase of ROS production. The increased level of ROS induced the assembly of an NLRP3 inflammasome and activated caspase-1. They also found that HeLa cells overexpressing GSDMB exhibit distinct pyroptotic properties 
. Besides, GZMB released from immune cells cleaves GSDME and promotes pyroptosis of HeLa cells, which is a crucial finding to deduce the connection between GSDM family-mediated cell death and the immune system 
. GSDME can also be cleaved by activated caspase-3, which removes the intramolecular inhibition of the GSDME-N domain, and GSDME-N has the same effect as GSDMD-N to cause formation of pores in the plasma membrane and pyroptosis 
Undifferentiated keratinized cells (KCs) in the basal layer of squamous epithelium are the main target cells of HPV infection, and PRR mediated signaling in these cells activates the innate immune system to fight infection 
. KCs are not only the primary target of HPV infection, but also the part-time immunoreactive cells in the central mucosa. KCs can express and assemble inflammasomes like neutrophils, macrophages and dendritic cells and secrete IL-1β through pyroptosis to resist viral infection 
. Expression of IL-1β in the cervical cancer group was observably lower compared with that in the normal control group and low-grade squamous intraepithelial lesion group, and women with low IL-1β expression had a higher risk of precancerous lesions progressing to cancer 
. This is related to HPV-mediated immune evasion 
. In the precancerous stage of HPV-infected cells, AIM2 plays a tumor suppressor role by activating caspase-1 to promote pyroptosis of tumor cells 
. Upregulation of microRNA-214 (MiR-214) in cervical cancer patients and cervical cancer cell lines promotes pyroptosis of cervical cancer cells by enhancing NLRP3 expression 
. These findings demonstrate that pyroptosis plays an inhibitory effect on the initiation and progression of cervical cancer.
However, there are also studies showing that pyroptosis, as a form of cell death accompanied by inflammation, provides a suitable microenvironment for tumor growth. Important factors in the process of pyroptosis, such as inflammasomes, gasdermin proteins and pro-inflammatory immune molecules, are involved in tumorigenesis, invasion and metastasis 
. Being a serine protease and pro-inflammatory factor, GZMB can affect the tumor microenvironment (TME) and promote cancer progression 
. GZMB has been found to be expressed in urothelial, melanoma and pancreatic cells, which is thought to contribute to cancer invasion 
. Moreover, the expression of GZMB in tumor tissues was significantly up-regulated and this expression of GZMB negatively correlated with the survival of patients with cervical cancer 
Therefore, pyroptosis in cervical cancer microenvironments might act as a two-edged sword in the progression of the cancer. In the early stage, pyroptosis causes death of tumor cells, which suppresses the progression of cancer. While in the advanced stage, the inflammatory mediators released from pyroptosis might deteriorate inflammation, and pyroptosis of immune cells themselves in the TME compromise their antitumor immune function, thereby promoting mainly cancer progression and metastasis. It requires more preclinical and clinical studies to further evaluate the complicated role of pyroptosis in the progression of cervical cancer.
2. Pyroptosis in the Diagnosis and Prognosis of Cervical Cancer
Early diagnosis and treatment are crucial to improve the prognosis and survival of patients with cervical cancer. Pyroptosis can regulate cell proliferation, differentiation, invasion and chemotherapeutic drug sensitivity through multiple signal pathways, thus affecting tumor development and is related to the prognosis of patients 
. Wang et al. integrated the complete set of pyroptosis-related genes (PRGs) and determined the expression changes of PRGs in more than 10,000 cancer cases based on TCGA data 
. They found that there were significant changes in the expression of PRGs in different types of cancer, but the expression of PRGs did not always correlate with the survival of patients 
. Therefore, pyroptosis may play different roles in different cancer types. An immunocorrelation analysis showed that the PRGs, including CHMP4C, TNF and GZMB, were closely related to the tumor immune microenvironment, thereby influencing the progression of cervical cancer 
. Patients with high TME scores exhibit stronger anti-tumor immune responses, with higher prognosis and survival rates after immunotherapy 
. In addition, progression of pyroptosis can remodel the TME and activate a strong immune cell-mediated anti-tumor response, which in turn plays a strong tumor suppressor effect 
. These studies demonstrate that when considered as an intrinsic immune mechanism, pyroptosis restrains tumorigenesis and progression, and is beneficial for prognosis and survival.
However, there are also studies showing that pyroptosis is negatively correlated with prognosis. High expression of IL-1β is associated with shorter survival in cervical, gastric and colorectal cancers 
. Earlier studies found that HeLa cells exhibited distinct characteristics of pyroptosis by expressing GSDMB 
. In the tumor tissues of patients with advanced cervical cancer, the expression of GZMB was significantly up-regulated 
. The prognostic correlation analysis of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) showed that high expression of GZMB was negatively correlated with survival 
. Therefore, pyroptosis has both positive and negative effects on the development of cervical cancer, and it is worthy of further exploring the value of pyroptosis in the diagnosis and prognosis of patients with cervical cancer.
3. Application of Pyroptosis in the Treatment of Cervical Cancer
Although there are controversial reports on the role of pyroptosis in the initiation and progression of cervical cancer, it is generally accepted that inducing pyroptosis of the cancer cell is an effective strategy to treat cancer.
3.1. Lobaplatin Induces Pyroptosis in Cervical Cancer Cells
As the aforementioned description, pyroptosis mediated by GSDMD-N is typically found in immune cells to respond to inflammatory stimulation, while the one mediated by GSDME-N was lately reported in chemotherapy treated cells 
. GSDME belongs to the gasdermin superfamily and can be cleaved by caspase-3 
. The function of GSDME in the pathogenesis of human tumors has been paid intensive attention. GSDME was considered as a tumor suppressor gene; for example, decreased expression of GSDME mRNA is associated with increased etoposide resistance in melanoma cells 
Lobaplatin is a commonly used chemotherapeutic drug and is widely used to treat diverse malignancies, involving cervical cancer, breast cancer, ovarian cancer and so on 
. Chen et al. demonstrated that lobaplatin induces cervical cancer cell pyroptosis through the caspase-3-GSDME pathway 
. Lobaplatin activates caspase-3, which subsequently facilitates the cleavage of GSDME and consequently induces pyroptosis. In addition, inhibiting the expression of GSDME significantly suppressed lobaplatin-induced pyroptosis.
3.2. Tanshinone IIA Induces Pyroptosis in Cervical Cancer Cells
Cisplatin or lobaplatin combined with radiotherapy is the main cytotoxic drug for the treatment of advanced cervical cancer and is considered to be the standard treatment for cervical cancer 
. However, it was reported that cervical cancer is resistant to chemotherapy and the efficacy of a single drug is often not durable 
Tanshinone IIA is a compound extracted from Salvia miltiorrhiza, with multi-biological activities, including antibacterial, anti-inflammatory and antitumor activities 
. Tanshinone IIA can inhibit malignant proliferation, enhance the death of malignant cells and significantly eliminate them. Tanshinone IIA treatment suppresses the proliferation of cervical cancer cells by repressing the HPV oncogenes and reactivating p53-dependent cancer suppressor genes 
MiRs are a family of non-coding RNAs that are included in almost all growth and development processes in human bodies 
. By regulating downstream targets, MiRs can act as tumor suppressor genes or oncogenes. Studies have shown a strong correlation between MiR-145 and inflammation 
. Zhang et al. revealed that tanshinone IIA inhibited the proliferation and inflammation of HeLa cells, which were associated with the switch between apoptosis and pyroptosis 
. They found that tanshinone IIA inhibited apoptosis by up-regulating the expression of GSDMD in HeLa cells and the expression of caspase-1 was markedly up-regulated after administration, which promoted the occurrence of pyroptosis, leading to increased levels of IL-18 and IL-1β. At the same time, tanshinone IIA up-regulated the expression of MiR-145 in HeLa cells at the mRNA level and therefore the inhibition of GSDMD expression was relieved 
. Therefore, regulation of MiR-145 and GSDMD in HeLa cells are tightly related to the anticancer activity of tanshinone IIA, providing potent evidence suggesting that tanshinone IIA is a potential anticancer drug for the therapy of cervical cancer.
3.3. Negative Effects of Pyroptosis on Tumor Treatment
It has been shown that the way chemotherapeutic drugs induce cell death is related to the expression level of GSDME. Chemotherapeutic drugs induced apoptosis in cells with low GSDME expression and pyroptosis in cells with high GSDME expression 
. However, scientists also pointed out that because of methylation, GSDME is under-expressed in most tumor cell lines, while it is generally over-expressed in normal cell lines 
. Thus, chemotherapy can also lead to pyroptosis of normal cells with high level GSDME, which might be the reasonable ground for chemotherapy-related toxic side effects. This was supported by the study in GSDME knock out mice. Pyroptosis was induced by intraperitoneal injection of cisplatin in wild-type mice, in which severe intestine damage could be observed, while gastrointestinal tissue damages were remarkably reduced in GSDME knockout mice 
Pyroptosis is also correlated with the negative effects of radiotherapy. Upon radiation treatment, the AIM2 inflammasome induces caspase-1-mediated pyroptosis of myeloid cells and intestinal epithelial cells, resulting in gastrointestinal injury and toxemia 
. Therefore, inhibiting the AIM2 inflammasome may alleviate the side effects of radiotherapy. Since radiation also triggers the pyroptosis of bone marrow macrophages mediated by the NLRP3 inflammasome, targeted inhibition of NLRP3 may also be a viable therapeutic strategy 
. These studies reveal the negative effects of pyroptosis in cancer treatment and provide new insights into chemotherapy and radiotherapy for cancers.