In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune "cold" tumors into "hot" tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy. 

/pdf/autophagy-ferroptosis-pyroptosis-and-necroptosis-in-tumor-191xb91c.pdf

Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy

Gasdermin D in pyroptosis.

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes. 

/pdf/regulated-cell-death-rcd-in-cancer-key-pathways-and-targeted-1zhjnd92.pdf

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Pyroptosis is a form of programmed cell death mediated by gasdermin and is a product of continuous cell expansion until the cytomembrane ruptures, resulting in the release of cellular contents that can activate strong inflammatory and immune responses. Pyroptosis, an innate immune response, can be triggered by the activation of inflammasomes by various influencing factors. Activation of these inflammasomes can induce the maturation of caspase-1 or caspase-4/5/11, both of which cleave gasdermin D to release its N-terminal domain, which can bind membrane lipids and perforate the cell membrane. Here, we review the latest advancements in research on the mechanisms of pyroptosis, newly discovered influencing factors, antitumoral properties, and applications in various diseases. Moreover, this review also provides updates on potential targeted therapies for inflammation and cancers, methods for clinical prevention, and finally challenges and future directions in the field. 

/pdf/role-of-pyroptosis-in-inflammation-and-cancer-1pq50gfr.pdf

Role of pyroptosis in inflammation and cancer

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2-(anaphthoyl)ethyltrimethylammonium iodide (α-NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin-d (GSDMD)/caspase-4 pathway. Furthermore, Cell Counting Kit-8 fluorescence-activated cell sorting analysis showed that α-NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with α-NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. α-NETA also significantly increased expression of pyroptosis-associated molecules including caspase-4 and GSDMD in EOC cells. Knockdown of either caspase-4 or GSDMD in ovarian cancer cells strongly interfered with α-NETA cell-killing activity, indicating that α-NETA acts through the pyroptosis pathway. In vivo, α-NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that α-NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy.-Qiao, L., Wu, X., Zhang, J., Liu, L., Sui, X., Zhang, R., Liu, W., Shen, F., Sun, Y., Xi, X. α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201900483RR

α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway

Background: Homologous recombination (HR) pathway defects in cancers induced abrogation of cell-cycle checkpoints resulting the accumulation of DNA damage, mitotic catastrophe and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers especially ovarian cancer. Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. Weighted Gene Co-Expression Network Analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting role in patients overall survival (OS) with univariate and multivariate Cox regression analysis and built the predicting model for patient survival. Results: We found that HRD score increased with the rising of tumor stage except for stage IV. HRD score tended to grow up higher in recurrent tumor tissue than in primary counterpart (p=0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting HRD score and concluded that HRD score was tightly associated with tumor cells replication and proliferation. Combined HRD score ≥42 was associated with shorter OS in altogether 33 cancer types (HR=1.010, 95%CI: 1.008-1.011, p <0.001). However, in ovarian cancer which ranked the highest HRD score among cancers, HRD ≥42 cohort was significantly associated with longer OS (HR=0.99, 95%CI:0.98-0.99, p<0.0001). We also built a predicting model for the 3-year and 5-year survival in HGSC patients. Conclusion: Quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells, since HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.

Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer

This study was conducted to evaluate the prognostic value of receptor-interacting protein kinase 4 (RIPK4) in ovarian cancer (OC) and its role in tumorigenesis. RNA expression and the corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The relationship between clinical-pathological characteristics and RIPK4 expression was analyzed using the Wilcoxon signed-rank test and logistic regression. The Cox regression and the Kaplan-Meier method were used to evaluate the relationship between clinicopathological features and overall survival (OS). Gene set enrichment analysis (GSEA) was performed using Molecular Signatures Database. Scratch assay, transwell assay, and cell transfection were used to verify the function of RIPK4. Overexpression of RIPK4 was associated with the stage of OC and distant metastasis. Survival analysis revealed that patients with OC and higher expression of RIPK4 had a poorer prognosis. Univariate and multivariate analyses indicated that high expression of RIPK4 was associated with poor OS, as well as age and stage of OC. The areas under the curve (AUC) at 1, 4, and 8 years were 0.737, 0.634, and 0.669, respectively, according to the established OS prediction model. GSEA revealed that adherens junction, cadherin binding, and Wnt signaling pathway were enriched in the high RIPK4 expression group. Cell transfection confirmed RIPK4 was involved in the Wnt signaling pathway. RIPK4 can act as a potential prognostic molecular marker for poor survival in OC. Moreover, RIPK4 is associated with tumor metastasis and implicated in the regulation of the Wnt signaling pathway.

/pdf/overexpression-of-ripk4-predicts-poor-prognosis-and-promotes-3256ok6xcp.pdf

Overexpression of RIPK4 Predicts Poor Prognosis and Promotes Metastasis in Ovarian Cancer.

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α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway

Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer

Overexpression of RIPK4 Predicts Poor Prognosis and Promotes Metastasis in Ovarian Cancer.