Reviews & Analysis

Clonal evolution is now a central theoretical framework in cancer research. In this Perspective, Laplane and Maley identify challenges to that theory such that some non-evolutionary phenomena in cancer cannot be captured by the theory. They also outline how other challenges, including non-genetic heredity, phenotypic plasticity, reticulate evolution and clone diversity, can be included in an expanded cancer evolutionary theory.

In this Review, Arpinati et al. summarize how the extracellular matrix, produced primarily by cancer-associated fibroblasts, impacts tumour progression, metastasis and therapy response through modulation of T cell-mediated antitumour immunity and propose routes to target these mechanisms therapeutically.

Resistance to therapy remains the biggest challenge to achieving cures in patients with cancer. In this Roadmap, Russo et al. overview the field of cancer drug-tolerant persister cells providing paths to advance our understanding of their biology with innovative technologies and recommend strategies to therapeutically target them to ensure that more prolonged responses are achieved in patients with cancer.

Various strategies have been proposed and implemented to target the tumour vasculature, which supports tumour growth and progression. However, to date they have had variable success. Guelfi et al. describe some of these approaches and discuss how our increased understanding of the interactions between tumour vessels and the immune compartment could help generate combination therapies that provide durable responses in patients with cancer.

Transient ectopic lymphoid structures known as tertiary lymphoid structures (TLS) have been observed in many solid tumour types. In this Review, Teillaud et al. discuss how these TLS potentially orchestrate immune responses against tumours locally and are positively associated with prognosis and response to immune checkpoint inhibitors. The authors also outline how preclinical studies are highlighting the potential to manipulate the formation and function of TLS as a novel form of immunotherapy.

Circular RNAs, once considered by-products of splicing errors, are now accepted as key players in cancer biology. In this Review, Conn et al. review the functional interactome of circular RNAs in cancer, highlighting their contribution to oncogenesis, their potential as biomarkers and the prospect of leveraging them for novel therapeutics.

Adoptive cell therapies have emerged as promising approaches for the treatment of patients with cancer. Engineering cell therapies to confer resistance to small-molecule therapies, chemotherapies and antibody-based therapies will improve their utility and success. Here, Wellhausen, Baek and colleagues outline the key principles of engineering resistance and potential applications for haematopoietic stem cell transplantation and allogeneic immune cell therapies.

Despite the success of immune-checkpoint inhibitors, many patients are at risk of developing immune-related adverse events. One of these is myocarditis or inflammation of the heart. Munir, Gutierrez and colleagues describe the data from preclinical models and patient samples, which have begun to provide a mechanistic understanding of myocarditis resulting from immune-checkpoint inhibitors, and present suggestions for improving both the diagnosis and treatment of patients experiencing this immune-related toxicity.

In this Review, Polak, Zhang and Kuo discuss the currently available and rapidly evolving 3D tumour organoid models that capture the tumour immune microenvironment. They highlight opportunities for organoid-based investigations of tumour immunity, drug development and precision medicine.

In this Review, Harris et al. summarize the dynamic changes of the immune breast tumour microenvironment (TME) that take place during disease progression and in response to treatment, and outline emerging therapies to target the immune TME in patients with breast cancer.

In this Roadmap, Boire et al. consider the immediate causes of mortality in patients with cancer, a topic not often considered in either preclinical or clinical research, and provide recommendations for how we can stimulate research to advance our mechanistic understanding of these causes with a long-term view to improving the quality of life for patients with late-stage cancer.

Although there has been increasing interest in developing models that mimic the tumour microenvironment (TME), these models often fail to replicate the complex 3D fibre architectures observed in tumours. Here, Ashworth and Cox address this, discuss the current design and fabrication challenges, and outline state-of-the-art biomaterial technologies useful for recreating tissue-specific 3D architectures in vitro.

The tumour immune microenvironment greatly affects responses to immune checkpoint therapies. In this Perspective, Zemek et al. explore the dynamic changes in response to both immunotherapy and conventional treatment and advocate for strategic combination therapies over time to enhance antitumour immune responses.

Metastasis to the leptomeninges causes substantial neurological morbidity and mortality. Owing to the lack of mechanistic studies in this area, patients still face a bleak clinical prognosis. In this Review, Remsik and Boire provide a biology-focused overview of recent developments enabled by preclinical models and omics analyses and outline the need for further mechanistic research on leptomeningeal metastasis.

In this Perspective, Holder et al. discuss the limitations of current predictive biomarkers of response to immune checkpoint inhibitors and the need to further explore static, dynamic and patient-specific biomarkers using novel tools, such as machine learning and consortia-level initiatives.

This Review provides an introductory guide to artificial intelligence (AI)-based tools for non-computational cancer researchers. Here, Perez-Lopez et al. outline the general principles of AI for image analysis, natural language processing and drug discovery, as well as how researchers can get started with each of them.

In this Review, Paul et al. provide an overview of therapeutic antibodies as an important modality in cancer therapy today. They summarize the different approaches used by antibodies to target cancer cells including those of immune checkpoint inhibitors, bispecific antibodies and antibody–drug conjugates, as well as describing current strategies aimed at improving their efficacy and reducing toxicities.

In this Review, Zhang and colleagues provide an overview of the molecular characteristics of paediatric cancer and highlight how these malignancies arise from developmental aberrations resulting in paediatric-specific cancer genomes that influence both the initiation and progression of cancer. Additionally, they discuss genetic vulnerabilities within these cancer genomes that present opportunities for therapeutic interventions.

In this Review, Cichowski and colleagues provide an overview of combinatorial strategies designed to treat RAS-driven cancers that are based on four concepts that include vertical pathway inhibition, co-targeting RAS and adaptive survival pathways, co-targeting downstream or converging pathways and capitalizing on other cancer-associated vulnerabilities.

Tumour-associated lymphatic growth and remodelling were once viewed as a passive means by which cancer cells could regionally spread to lymph nodes. However, recent data point to an active and contrasting role for lymphatic vessels and their transport in antitumour immune surveillance. In this Review, Karakousi et al. provide a working framework to define this role for the lymphatic system in tumour progression and present avenues for its therapeutic manipulation to improve cancer immunotherapy.