20th Anniversary

This issue marks the 20th anniversary of Nature Reviews Cancer. On this milestone birthday we both look back on the past 20 years of cancer research and look forward to the future.

Significant gaps in access to care have shifted the burden of cervical cancer disease to resource-poor countries in Africa, Asia and Latin America. The recent World Health Organization’s Call to Action to eliminate cervical cancer is a unique opportunity to galvanize change and remove barriers to prevention and care.

A systematic approach to understanding the noncoding genome in cancer promises to improve cancer diagnosis and therapy. New technologies and bold therapeutic approaches are paving the way to truly envisage personalized cancer medicine in the future.

Based on a virtual discussion during the American Association for Cancer Research (AACR) 2020 Annual Meeting, we asked several scientists actively working to improve representation of Black American populations in cancer research how they are addressing these issues.

Mutational signatures can provide insights into the origins and vulnerabilities of specific cancers, and have potential for clinical utility. This Review highlights recent developments in the field, providing insights into practical issues and challenges in mutational signature analysis.

The development of small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) has made it possible to target oncoproteins previously considered undruggable. This Review discusses recent advances in the field, with a focus on opportunities and challenges for future development.

Synthetic biomarkers are an emerging class of diagnostics that amplify disease signals for sensitive and specific detection of early-stage cancers. This Review discusses the rationale and design of biofluid-based synthetic biomarkers as well as translational challenges and future directions.

This Perspective discusses the main themes in cancer metabolism research that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing emerging aspects and questions that remain unanswered.

Clonal expansion in phenotypically normal or non-cancer tissues is commonly seen in association with ageing and/or in response to environmental insults and chronic inflammation, but does not necessarily indicate cancer development. This Review discusses recent findings on clonal expansion in these tissues and their biological significance in cancer development, ageing and inflammatory diseases.

The majority of cancers arise in individuals over the age of 60. This Review discusses how ageing tissues through changes in the extracellular matrix as well as in the functions of fibroblasts and immune cells can impact tumour initiation, progression and response to therapy.

This Perspective highlights the evidence from basic and translational research that genetic sex influences multiple factors that can contribute to cancer development and treatment responses, and suggests that including genetic sex considerations in treatments for patients with cancer will improve outcomes.

This Review discusses how fly tumours interact with the microenvironment and distant organs to influence disease progression and host physiology. The authors argue that the simplicity of flies and the ability to study lethality in this model provide an opportunity to address why patients ultimately die of cancer.

In vitro cancer models often fail to faithfully recapitulate the local tissue and organ microenvironment. Organs-on-chips can overcome this limitation and better mimic in vivo cancer phenotypes. This Review outlines the advances that have been made with this technology and explains the challenges that must be overcome to see its implementation into drug development pipelines and clinical cancer care.

After synthesis, all RNA molecules are subject to covalent modifications. This Review presents the evidence that RNA modification pathways are misregulated in cancer and suggests that they may be ideal targets for cancer therapy.

In this Perspectives article, the authors outline the preclinical and clinical evidence for epithelial–mesenchymal plasticity (EMP) in cancer progression and metastasis, focusing on recent challenges and controversies, and highlight strategies to therapeutically target the EMP process.

This Perspective discusses how therapeutic resistance is not only driven by genetic evolution but often involves non-genetic adaptive mechanisms that are intimately linked. Acknowledging these adaptive processes will enable the development of innovative strategies to monitor and counteract non-genetic therapy resistance as well as provide novel therapeutic avenues.

This Review provides a brief historical perspective of our understanding of the role of cancer genes before presenting the Integrative OncoGenomics (IntOGen) platform, a bioinformatics method of mutational driver identification, which is beginning to reveal the compendium of driver genes across many tumour types as well as alluding to their tumorigenic mechanisms.

This Review discusses functional screening strategies in mice, which use genetic perturbation or chemical mutagenesis to delineate genomic and regulatory features in oncogenesis, metastasis and drug resistance, which might in turn help to identify targetable cancer vulnerabilities.

Alterations in the extracellular matrix at the biochemical, biomechanical, architectural and topographical levels contribute to the development and progression of solid tumours. Our increased understanding of matrix biology is leading to the development of new approaches that co-target the matrix in cancer, including in metastasis.

This Perspective proposes operational definitions to define the hallmarks of cancer cell dormancy and, based on the latest evidence pertaining to the role of the microenvironment in regulating dormancy, presents key stages in the life cycle of a dormant cancer cell that could be targeted.

This Review discusses the role that nerves play in the initiation and progression of cancers, focusing on the evidence that tumours may reactivate nerve-mediated developmental and regenerative pathways to promote their own growth and survival.

This Consensus Statement highlights the importance of cancer-associated fibroblasts in cancer biology and progression, and issues a call to action for all cancer researchers to standardize assays and report metadata in studies of cancer-associated fibroblasts to advance our understanding of this important cell type in the tumour microenvironment.

This Review discusses the structure and function of the blood–brain barrier (BBB) and how brain tumours and brain metastases compromise BBB integrity. It also discusses the challenges the BBB poses for cancer therapy and how these might be overcome.

This Review examines the tissue-specific metabolism and associated therapeutic vulnerabilities of mutant KRAS-driven tumours, providing a comparative discussion of intrinsic metabolism, co-occurring mutations and metabolic interactions in the microenvironment in colorectal, lung and pancreatic cancer.

This Review describes the metabolic rewiring that occurs in cancer cells transitioning through the metastatic cascade and discusses the evidence for metabolically distinct features of primary tumours and metastases.

This Review discusses our current understanding of adaptive and innate immune cell metabolism in the context of the tumour microenvironment, providing insight into the interaction of cancer cell metabolism and immune metabolism, as well as the potential for leveraging metabolic vulnerabilities to enhance the antitumour immune response.

An improved understanding of tumour immunology and therapy must assess the systemic immune landscape beyond the tumour microenvironment. This Review outlines peripheral immune cell reorganization in response to tumour growth and therapy, their contribution to immunotherapy responses and their potential as diagnostic or predictive biomarkers.

This Review broadly discusses therapeutic cancer vaccines, covering resistance mechanisms and strategies to overcome these, how to improve the antigen repertoire for vaccines and vaccine platforms, and approaches for enhancing immunotherapy efficacy.

This Review outlines the major advances that have been made to the efficacy and safety of chimeric antigen receptor (CAR) T cell therapies over the past 3 years and looks to new findings that will have consequences for the future of this immunotherapy.

This Review discusses the key role that natural killer (NK) cells play in driving an antitumour immune response throughout the progression of cancer from its initial development to its metastatic spread and eventual treatment, defined herein as the cancer–NK cell immunity cycle.

Innate immune checkpoints, including those regulating tumour detection and phagocytosis, have emerged as potential cancer immunotherapy targets. This Review discusses the role of phagocytosis checkpoints in cancer immune evasion, highlighting the preclinical and early clinical evidence supporting phagocytosis checkpoint blockade.

In addition to cancer cell-intrinsic effects, tumour growth can be regulated by cellular and molecular cues from the local tissue environment. This Review discusses how differences in cellular components and composition between tissue sites may influence the antitumour immune response, with potential implications for the design of therapeutic strategies.

This Review discusses recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, programmed cell death 1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome.

How does a Nature Reviews Cancer Review or Perspectives article move from an idea to a published article? Here, in the spirit of transparency, we provide some insights into this process.

Opinions on where we should progress next with cancer research are diverse. In this article, four top cancer researchers from across the globe discuss their thoughts on the current state of cancer research and what progress might be expected in the next 10 years.

In this Viewpoint article, we asked four female scientists to describe their experiences of gender representation during their scientific careers and to identify the challenges and possible solutions to empowering women in cancer research and science more generally.

In this Viewpoint, we have asked recipients of the Nature Awards for Mentoring in Science about their views on good mentoring, and how mentorship can help to achieve a positive research culture and contribute to scientific discovery in cancer research.

There is evidence of a mounting mental health crisis among researchers, which may be exacerbated by the COVID-19 pandemic. This Comment article discusses what cancer researchers and institutions can do to promote good mental health and wellbeing within their research communities.

In an effort to prevent bullying and harassment in the research sector, funding bodies have introduced policies to promote a positive research culture. Here, Sue Russell and Iain Foulkes comment on what this means for researchers.

The use of social media for the dissemination of published and unpublished scientific findings has exploded over the past few years. In this Comment article, Soragni and Maitra explain some of the ways in which Twitter can be used by academics to promote their science.

Black people have the highest cancer rates in the USA owing to systemic racism — biased systems that put pressure on Black lives every day. STEM scholars have a responsibility to reduce the historical trauma associated with systemic racism. This also means challenging systemic racism within STEM fields.

The number of people disclosing gender diverse identities is growing. We must act now to collect data on cancer incidence and outcomes, and promote inclusion in studies, in order to better understand cancer in this population and provide equitable cancer care.

Cancer genomics research in Africa is crucial to understanding the genetic architecture of cancer and tailoring cancer diagnoses and therapies to African populations. Creating this research enterprise in Africa has to be purposeful with a roadmap that incorporates individual scientist-, international collaborator-, university or institution-, and scientific organization-level factors.

This Comment article argues that genomic, epigenomic and other studies on cancer in diverse populations across low-income and middle-income countries are essential in order to reduce worldwide cancer burden and improve global health.

In this Viewpoint article, we asked four experts to share their thoughts on the implementation of artificial intelligence and machine learning techniques into cancer research and care, and how to separate the hope from the hype to overcome the challenges ahead.

In this Viewpoint article, we asked four scientists working in the field of epithelial to mesenchymal transition (EMT) to provide their opinions on the role of this complicated phenomenon in cancer biology as well as the challenges of this fast-moving field and the directions it should take in the future.

In this Viewpoint article, we asked four scientists working on the cancer microbiome to provide their opinions on the current state of the field, where the research is heading and the challenges of implementing this field for clinical utility.

In this Viewpoint article, we asked four scientists working to target important, but so-called 'undruggable', proteins in cancer for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of cancer research.

Many patients have now received various types of immunotherapy, so we asked three scientists to give their views on whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy.

This Review discusses mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and molecularly targeted therapies, which share many features. It is hoped that an improved understanding of the molecular basis of resistance will lead to rational drug combinations and predictive biomarkers.

Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis, as well as new targets for cancer therapy. Which of the discoveries in the past 10 years are ready for advancement?

Circulating tumour DNA (ctDNA) analysis has the potential to improve prognostication, molecular profiling and disease monitoring in patients with cancer. This Review summarizes recent advances, potential applications in cancer research and personalized oncology, and the introduction of ctDNA into clinical use.

MicroRNAs (miRNAs) are small, non-protein-coding RNAs that can repress the expression of important cancer-related genes. The mutation or mis-expression of several miRNAs is evident in human cancers, so will these novel RNAs prove useful in the diagnosis and treatment of cancer?

Research into the DNA damage response (DDR) was recently honoured by the Nobel Prize in Chemistry and the Lasker Award. In this Timeline article, the authors provide a historical perspective on our understanding of the role of the DDR in cancer.

In this Opinion article, Schneideret al. outline tissue- and cell type-specific differences in tumorigenesis and the organization of oncogenic signalling pathways, and discuss the implications of our understanding of tissue context on molecularly targeted therapy and clinical trial design.

Neoplasms are microcosms of evolution. The evolution of neoplastic cells explains why we get cancer and why it has been so difficult to cure. Can evolutionary biology provide new insights into the clinical control of cancer?

Populations of tumour cells display remarkable phenotypic diversity as a result of both genetic and non-genetic influences. This Review discusses underlying causes of this intra-tumour phenotypic heterogeneity, and why this phenomenon may affect our ability to diagnose and effectively treat tumours.

The integrins regulate a diverse array of cellular functions that are crucial to the initiation, progression and metastasis of solid tumours. This Review discusses the exciting developments in targeting integrins, including the recent initiation of a Phase III trial for an integrin antagonist in patients with glioblastoma.

There is increasing debate about what is meant by the term 'cancer stem cell' (CSC) and the degree to which the concept of CSCs can provide insights into cancer biology and therapy. This Timeline article traces the historical milestones in normal and cancer stem cell biology as a backdrop to a discussion of how these fields have informed each other.

Fibroblasts are an important component of the tumour microenvironment. They become activated in tumours, as they do in healing wounds. Here, their roles in tumour initiation, progression and metastasis are reviewed.

This Review discusses the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

Metastatic dissemination and growth at distant sites are influenced by cells of the tumour microenvironment. What roles do these cells have in the underlying processes that determine metastatic growth?

Fundamental differences in the regulation of central metabolic pathways exist between tumours and normal tissue. This Review discusses how the Warburg effect is still applicable to our view of cancer metabolism and new advances in understanding beyond this hypothesis, including regulating anapleurosis and the redox balance.

Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

This Perspective discusses some of the causes of the robustness and reproducibility problem in preclinical cancer research and suggests solutions.

This Review summarizes progress in applying nanotechnology to cancer treatment and discusses the challenges of clinical translation and opportunities to develop more effective nanotherapeutics through our increasing understanding of tumour biology and nano–bio interactions.