Showing papers in "Nature Reviews Cancer in 2022"
TL;DR: The current understanding of ferroptosis-inducing and ferroPTosis defence mechanisms is summarized, the roles and mechanisms of ferraptosis in tumour suppression and tumour immunity are dissected, and therapeutic strategies for targeting ferroaptosis in cancer are explored.
314 citations
TL;DR: The responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves.
219 citations
TL;DR: In this article , the authors discuss how senescence can be induced in cancer cells and how distinctive features of senescent cancer cells might be exploited for their selective eradication as a potential cancer therapy.
Abstract: Senescence is a cellular response to a variety of stress signals that is characterized by a stable withdrawal from the cell cycle and major changes in cell morphology and physiology. While most research on senescence has been performed on non-cancer cells, it is evident that cancer cells can also mount a senescence response. In this Review, we discuss how senescence can be induced in cancer cells. We describe the distinctive features of senescent cancer cells and how these changes in cellular physiology might be exploited for the selective eradication of these cells (senolysis). We discuss activation of the host immune system as a particularly attractive way to clear senescent cancer cells. Finally, we consider the challenges and opportunities provided by a ‘one-two punch’ sequential treatment of cancer with pro-senescence therapy followed by senolytic therapy. This Review discusses how senescence can be induced in cancer cells and how distinctive features of senescent cancer cells might be exploited for their selective eradication as a potential cancer therapy.
153 citations
TL;DR: In this article , the authors describe various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.
Abstract: Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.
95 citations
TL;DR: A review of the progress made in the development of CRISPR systems as a tool to study cancer, and the emerging adaptation of these technologies to improve diagnosis and treatment can be found in this article .
Abstract: Over the past decade, CRISPR has become as much a verb as it is an acronym, transforming biomedical research and providing entirely new approaches for dissecting all facets of cell biology. In cancer research, CRISPR and related tools have offered a window into previously intractable problems in our understanding of cancer genetics, the noncoding genome and tumour heterogeneity, and provided new insights into therapeutic vulnerabilities. Here, we review the progress made in the development of CRISPR systems as a tool to study cancer, and the emerging adaptation of these technologies to improve diagnosis and treatment.
93 citations
TL;DR: Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.
86 citations
TL;DR: The recent discovery of cancer cell-intrinsic programmed death ligand 1 (PDL1) signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation as discussed by the authors .
Abstract: The paradigm of surface-expressed programmed death ligand 1 (PDL1) signalling to immune cell programmed death 1 (PD1) to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent. These insights demonstrate that the prevailing cell-extrinsic PDL1 signalling paradigm is useful, but incomplete in important respects. This Perspective discusses historical and recent advances in understanding cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as reliable treatment response biomarkers. Cancer cell-intrinsic PD1 signals and cell-intrinsic PDL1 signals in non-cancer cells are discussed briefly, as are PDL1 signals from soluble and vesicle-bound PDL1 and PDL1 isoforms. We conclude with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field.
85 citations
TL;DR: The recent discovery of cancer cell-intrinsic programmed death ligand 1 (PDL1) signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation as discussed by the authors .
Abstract: The paradigm of surface-expressed programmed death ligand 1 (PDL1) signalling to immune cell programmed death 1 (PD1) to inhibit antitumour immunity has helped to develop effective and revolutionary immunotherapies using antibodies blocking these cell-extrinsic interactions. The recent discovery of cancer cell-intrinsic PDL1 signals has broadened understanding of pathologic tumour PDL1 signal consequences that now includes control of tumour growth and survival pathways, stemness, immune effects, DNA damage responses and gene expression regulation. Many such effects are PD1-independent. These insights demonstrate that the prevailing cell-extrinsic PDL1 signalling paradigm is useful, but incomplete in important respects. This Perspective discusses historical and recent advances in understanding cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and important immunopathologic consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies. Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as reliable treatment response biomarkers. Cancer cell-intrinsic PD1 signals and cell-intrinsic PDL1 signals in non-cancer cells are discussed briefly, as are PDL1 signals from soluble and vesicle-bound PDL1 and PDL1 isoforms. We conclude with suggestions for addressing the most pressing challenges and opportunities in this rapidly developing field.
73 citations
TL;DR: The mechanisms underlying the immune response in the tumour are reviewed and recent advances are discussed, which suggest that other extrinsic factors, such as the microbiome, may play a role in theimmune response to melanomas.
69 citations
TL;DR: In this paper , the authors provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents.
Abstract: Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
60 citations
TL;DR: In this article , the authors reviewed the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to tumour-infiltrating B lymphocytes (TIL-Bs) in human cancer.
Abstract: Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically ‘hot’ tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy. This Review discusses our current understanding of tumour-infiltrating B lymphocytes (TIL-Bs) in human cancers, considering the role of TIL-Bs across the major facets of cancer immunity. The authors also discuss strategies to harness the cell-based and antibody-based effector mechanisms of TIL-Bs to enable a new generation of cancer immunotherapies.
TL;DR: In this paper , the formation of biomolecular condensates via liquid-liquid phase separation (LLPS) has recently emerged as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells.
Abstract: Cancer is a disease of uncontrollably reproducing cells. It is governed by biochemical pathways that have escaped the regulatory bounds of normal homeostatic balance. This balance is maintained through precise spatiotemporal regulation of these pathways. The formation of biomolecular condensates via liquid-liquid phase separation (LLPS) has recently emerged as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells. Biomolecular condensates are widely observed to directly regulate key cellular processes involved in cancer cell pathology, and the dysregulation of LLPS is increasingly implicated as a previously hidden driver of oncogenic activity. In this Perspective, we discuss how LLPS shapes the biochemical landscape of cancer cells.
TL;DR: In this paper , the authors describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment.
Abstract: Normal cells explore multiple states to survive stresses encountered during development and self-renewal as well as environmental stresses such as starvation, DNA damage, toxins or infection. Cancer cells co-opt normal stress mitigation pathways to survive stresses that accompany tumour initiation, progression, metastasis and immune evasion. Cancer therapies accentuate cancer cell stresses and invoke rapid non-genomic stress mitigation processes that maintain cell viability and thus represent key targetable resistance mechanisms. In this Review, we describe mechanisms by which tumour ecosystems, including cancer cells, immune cells and stroma, adapt to therapeutic stresses and describe three different approaches to exploit stress mitigation processes: (1) interdict stress mitigation to induce cell death; (2) increase stress to induce cellular catastrophe; and (3) exploit emergent vulnerabilities in cancer cells and cells of the tumour microenvironment. We review challenges associated with tumour heterogeneity, prioritizing actionable adaptive responses for optimal therapeutic outcomes, and development of an integrative framework to identify and target vulnerabilities that arise from adaptive responses and engagement of stress mitigation pathways. Finally, we discuss the need to monitor adaptive responses across multiple scales and translation of combination therapies designed to take advantage of adaptive responses and stress mitigation pathways to the clinic.
TL;DR: In this article , the authors provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents.
Abstract: Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.
TL;DR: In this article , the formation of biomolecular condensates via liquid-liquid phase separation (LLPS) has recently emerged as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells.
Abstract: Cancer is a disease of uncontrollably reproducing cells. It is governed by biochemical pathways that have escaped the regulatory bounds of normal homeostatic balance. This balance is maintained through precise spatiotemporal regulation of these pathways. The formation of biomolecular condensates via liquid-liquid phase separation (LLPS) has recently emerged as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells. Biomolecular condensates are widely observed to directly regulate key cellular processes involved in cancer cell pathology, and the dysregulation of LLPS is increasingly implicated as a previously hidden driver of oncogenic activity. In this Perspective, we discuss how LLPS shapes the biochemical landscape of cancer cells.
TL;DR: Applications of proteogenomics in translational studies and immuno-oncology are rapidly emerging, and the prospect for their full integration into therapeutic trials and clinical care seems bright.
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TL;DR: In this article , the authors asked four experts for their opinions on how we can fulfil the great promise of nanomedicine for the detection, diagnosis, and treatment of patients with cancer.
Abstract: The field of cancer nanomedicine seeks to overcome the inherent shortcomings of conventional cancer diagnostics and therapies. Yet despite the surge of interest in and attractive attributes of nanotechnologies, challenges remain in their clinical translation, prompting some to argue that they have not yet reached their true potential. In this Viewpoint article, we asked four experts for their opinions on how we can fulfil the great promise of nanomedicine for the detection, diagnosis and treatment of patients with cancer. In this Viewpoint article, we asked four scientists working in the field of cancer nanomedicine to provide their opinions on how we can truly fulfil the great promise of nanotechnologies for the detection, diagnosis and treatment of patients with cancer.
TL;DR: In this paper , the authors discuss carcinogens in smokeless tobacco products and cigarette smoke and biomarkers that may be able to identify those individuals at highest risk of tobacco-related cancers.
Abstract: Tobacco products present a deadly combination of nicotine addiction and carcinogen exposure resulting in millions of cancer deaths per year worldwide. A plethora of smokeless tobacco products lead to unacceptable exposure to multiple carcinogens, including the tobacco-specific nitrosamine N′-nitrosonornicotine, a likely cause of the commonly occurring oral cavity cancers observed particularly in South-East Asian countries. Cigarettes continue to deliver a large number of carcinogens, including tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons and volatile organic compounds. The multiple carcinogens in cigarette smoke are responsible for the complex mutations observed in critical cancer genes. The exposure of smokeless tobacco users and smokers to carcinogens and toxicants can now be monitored by urinary and DNA adduct biomarkers that may be able to identify those individuals at highest risk of cancer so that effective cancer prevention interventions can be initiated. Regulation of the levels of carcinogens, toxicants and nicotine in tobacco products and evidence-based tobacco control efforts are now recognized as established pathways to preventing tobacco related cancer. This Review discusses carcinogens in smokeless tobacco products and cigarette smoke and biomarkers that may be able to identify those individuals at highest risk of tobacco-related cancers. It also discusses regulation of the levels of carcinogens and nicotine in these products as approaches to cancer prevention.
TL;DR: This Review discusses the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomersase andALT.
TL;DR: The metabolic alterations and key vulnerabilities that occur across multiple types of cancer are reviewed and how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens are described.
TL;DR: Jiang et al. as discussed by the authors reviewed the current state of the art and future challenges for harnessing big data to advance cancer research and treatment, and discussed considerations and strategies for wielding "big data" in basic research and for translational applications such as identifying biomarkers, informing clinical trials and developing new assays and treatments.
Abstract: Historically, the primary focus of cancer research has been molecular and clinical studies of a few essential pathways and genes. Recent years have seen the rapid accumulation of large-scale cancer omics data catalysed by breakthroughs in high-throughput technologies. This fast data growth has given rise to an evolving concept of ‘big data’ in cancer, whose analysis demands large computational resources and can potentially bring novel insights into essential questions. Indeed, the combination of big data, bioinformatics and artificial intelligence has led to notable advances in our basic understanding of cancer biology and to translational advancements. Further advances will require a concerted effort among data scientists, clinicians, biologists and policymakers. Here, we review the current state of the art and future challenges for harnessing big data to advance cancer research and treatment. The increasing size of cancer datasets requires new ways of thinking for analysing and integrating these data. In this Review, Jiang et al. discuss considerations and strategies for wielding ‘big data’ ― large, information-rich datasets ― in basic research and for translational applications such as identifying biomarkers, informing clinical trials and developing new assays and treatments.
TL;DR: Findings suggest that NMD-modulatory therapy has the potential to provide widespread therapeutic benefit against diverse tumour types, however, whether NMD should be stimulated or repressed requires careful analysis of the tumour to be treated.
TL;DR: An overview of the complex biology of the KLK family and its context-dependent nature in cancer is presented, and the different therapeutic strategies available to potentially target these proteases are discussed.
TL;DR: A comprehensive overview of the fast-evolving field of PRRs in cancer is provided, and the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings is discussed.
TL;DR: The biological machinery used by brain tumour stem cells to commandeer tissues in the intracranial space, evade immune responses and resist chemoradiotherapy is reviewed.
TL;DR: This Perspective demonstrates by the example of glioblastomas and other incurable brain tumours how versatile multicellular tumour networks are formed by two classes of long intercellular membrane protrusions: tumour microtubes and tunnelling nanotubes.
TL;DR: Recent advances are reviewed and emerging strategies for microbiota-based cancer therapies are discussed, including faecal microbiota transplantation or dietary interventions that might be utilized clinically to improve the success rate of immunotherapy in patients with cancer.