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Cellular & Molecular Immunology May 2021Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination... (Review)
Review
Cell death is a fundamental physiological process in all living organisms. Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity. In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially. Different modalities of what has become known as 'programmed cell death' have been described, and some key players in these processes have been identified. We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death. These studies have highlighted the complex mechanisms tipping the balance between different cell fates. Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.
Topics: Animals; Apoptosis; Health; Humans; Inflammation; Models, Biological; Necroptosis; Pyroptosis
PubMed: 33785842
DOI: 10.1038/s41423-020-00630-3 -
Signal Transduction and Targeted Therapy Jun 2022In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many... (Review)
Review
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.
Topics: Autophagy; Ferroptosis; Humans; Immunologic Factors; Immunotherapy; Necroptosis; Neoplasms; Pyroptosis
PubMed: 35725836
DOI: 10.1038/s41392-022-01046-3 -
Trends in Cancer Jan 2022Necroptosis, a form of programmed necrotic cell death, is a gatekeeper of host defense against certain pathogen invasions. The deregulation of necroptosis is also a key... (Review)
Review
Necroptosis, a form of programmed necrotic cell death, is a gatekeeper of host defense against certain pathogen invasions. The deregulation of necroptosis is also a key factor of many inflammatory diseases. Recent studies have revealed an important role of necroptosis in tumorigenesis and metastasis and imply the potential of targeting necroptosis as a novel cancer therapy. While its molecular mechanism has been well studied, details of the regulation and function of necroptosis of tumor cells in tumorigenesis and metastasis only began to emerge recently, and we discuss these herein.
Topics: Apoptosis; Humans; Necroptosis; Necrosis; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 34627742
DOI: 10.1016/j.trecan.2021.09.003 -
Journal of Hematology & Oncology Dec 2022Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death... (Review)
Review
Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.
Topics: Humans; Cell Death; Neoplasms; Copper; Apoptosis; Ferroptosis; Pyroptosis; Necroptosis
PubMed: 36482419
DOI: 10.1186/s13045-022-01392-3 -
Nature Reviews. Neuroscience Jan 2019Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However,... (Review)
Review
Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
Topics: Animals; Brain; Humans; Inflammation; Necroptosis; Neurodegenerative Diseases; Neurons; Phosphorylation; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 30467385
DOI: 10.1038/s41583-018-0093-1 -
Immunological Reviews Sep 2020ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z-RNA... (Review)
Review
ZBP1 has been characterized as a critical innate immune sensor of not only viral RNA products but also endogenous nucleic acid ligands. ZBP1 sensing of the Z-RNA produced during influenza virus infection induces cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). PANoptosis is a coordinated cell death pathway that is driven through a multiprotein complex called the PANoptosome and enables crosstalk and co-regulation among these processes. During influenza virus infection, a key step in PANoptosis and PANoptosome assembly is the formation of the ZBP1-NLRP3 inflammasome. When Z-RNA is sensed, ZBP1 recruits RIPK3 and caspase-8 to activate the ZBP1-NLRP3 inflammasome. Several other host factors have been found to be important for ZBP1-NLRP3 inflammasome assembly, including molecules involved in the type I interferon signaling pathway and caspase-6. Additionally, influenza viral proteins, such as M2, NS1, and PB1-F2, have also been shown to regulate the ZBP1-NLRP3 inflammasome. This review explains the functions of ZBP1 and the mechanistic details underlying the activation of the ZBP1-NLRP3 inflammasome and the formation of the PANoptosome. Improved understanding of the ZBP1-NLRP3 inflammasome will direct the development of therapeutic strategies to target infectious and inflammatory diseases.
Topics: Apoptosis; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Necroptosis; Pyroptosis; RNA-Binding Proteins
PubMed: 32729116
DOI: 10.1111/imr.12909 -
Journal of Hematology & Oncology Aug 2020In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly... (Review)
Review
In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.
Topics: Adaptive Immunity; Alarmins; Animals; Antigens, Neoplasm; Autophagy; Ferroptosis; Humans; Immune Checkpoint Inhibitors; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Mice; Models, Immunological; NF-kappa B; Necroptosis; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms; Protein Kinases; Pyroptosis
PubMed: 32778143
DOI: 10.1186/s13045-020-00946-7 -
Cell Death & Disease Apr 2021Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use... (Review)
Review
Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.
Topics: Animals; Apoptosis; Autophagy; Cardiotoxicity; Doxorubicin; Humans; Myocytes, Cardiac; Necroptosis
PubMed: 33795647
DOI: 10.1038/s41419-021-03614-x -
Frontiers in Cellular and Infection... 2020Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for... (Review)
Review
Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.
Topics: Apoptosis; Humans; Necroptosis; Phylogeny; Pyroptosis
PubMed: 32582562
DOI: 10.3389/fcimb.2020.00238 -
Pharmacology & Therapeutics Apr 2022Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of... (Review)
Review
Programmed cell death (PCD) is an essential part of organismal development and plays fundamental roles in host defense against pathogens and the maintenance of homeostasis. However, excess activation of PCD pathways has proven to be detrimental and can drive disease. Additionally, resistance to PCD can also contribute to disease development. Modulation of PCD, therefore, has great therapeutic potential in a wide range of diseases, including infectious, neurodegenerative, autoinflammatory, and metabolic diseases and cancer. Nevertheless, manipulation of cell death and inflammation for therapeutic intervention is a delicate process, highly specific to the context of the disease of interest, making the selection of the appropriate target molecule crucially important. Several PCD pathways are associated with innate immunity, including pyroptosis, apoptosis, necroptosis, and PANoptosis, which is defined as an inflammatory PCD pathway with key features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these three PCD pathways alone. All of these PCD pathways are regulated by upstream sensors and signaling cascades that assemble multimeric complexes to serve as activation platforms for downstream molecules; these sensors and signaling molecules provide attractive target points for therapeutic intervention. Here, we discuss the molecular mechanisms of innate immune-mediated cell death in health and disease, with a particular focus on the molecules putatively involved in the formation of the PANoptosome and the induction of inflammatory cell death. Further, we discuss the implications and feasibility of targeting these molecules to improve disease outcomes, as well as current clinical approaches.
Topics: Apoptosis; Cell Death; Humans; Immunity, Innate; Necroptosis; Pyroptosis
PubMed: 34619283
DOI: 10.1016/j.pharmthera.2021.108010