Review Articles

Knowledge of the native T cell landscape and how it evolves under immunotherapeutic pressure will enable us to improve upon current clinical responses to immune-based interventions. In this Review, Oliveira and Wu outline how recent multidimensional single-cell studies have brought us a step closer to this goal by linking intratumoural phenotypes with the antigen specificity of T cells.

Overactive nucleotide synthesis is a hallmark of cancers and inhibitors of nucleotide synthesis pathways have shown promise in some cancer types. In this Review, Mullen and Singh give an overview of the role of aberrant nucleotide synthesis in supporting cancer cell growth, immune evasion, metastasis and resistance to cancer therapies, with a focus on identifying opportunities for the use of combination therapies to target these pathways more effectively.

Myeloid cells in the tumour microenvironment strongly influence tumour progression, and targeting these cells has been a key clinical focus. In this Review, Barry et al. discuss preclinical and clinical data on myeloid-targeting therapies, with a focus on how understanding context-specific effects might aid the design of successful clinical trials for these drugs.

This Review outlines how the profound intertumoural heterogeneity in immune landscapes of tumours is shaped by cancer cell-intrinsic alterations and highlights how the crosstalk between these two continuously evolving systems not only challenges therapy success of immunomodulatory drugs but also provides the basis for new therapeutic strategies to overcome immune evasion.

Acetyl coenzyme A (acetyl-CoA) is a key metabolite in carbohydrate and lipid metabolism and plays a role in signalling through protein acetylation, and the dysregulation of these pathways is a hallmark of various cancers. In this Review, Guertin and Wellen give an overview of acetyl-CoA metabolism in health and in cancer and discuss emerging therapeutic strategies for targeting metabolic pathways involving acetyl-CoA.

This Review discusses the diverse ways in which cancer-associated RNA splicing dysregulation promotes tumour initiation and progression, existing and emerging approaches for targeting splicing for cancer therapy and outstanding questions and challenges in the field.

Reprogrammed metabolism is a hallmark of cancer. Here, Li, Zhang and colleagues describe how signal transducer and activator of transcription (STAT) proteins alter cancer cell metabolism by sensing and transducing signals from the tumour environment and modulating signalling pathways, transcription factors, mitochondrial proteins and enzymes.

As well-established players in the metastatic cascade, circulating tumour cells (CTCs) hold promise for improved cancer diagnosis and disease monitoring. In this Review, Ring et al. overview the current understanding of CTC biology, highlighting specific opportunities and vulnerabilities for future CTC-focused therapies.

Genes encoding DNA damage response factors are frequently mutated in cancer, causing genomic instability and presenting opportunities for therapeutic intervention. This Review discusses state-of-the-art strategies for DNA damage response inactivation using small-molecule inhibitors.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and its incidence continues to rise, mostly owing to an increase in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. In this Review, the authors describe HPV-positive and HPV-negative HNSCC tumour microenvironments and discuss current and novel treatment modalities.

Pancreatic ductal adenocarcinomas are characterized by a robust stromal reaction. This Review discusses how the evolution of the epithelium in pancreatic cancers is coordinated with a programme of stromal progression; this comprehensive picture of tumour development might, in turn, point to new therapeutic vulnerabilities.

This Review covers recent advances in intravital imaging of mammalian models of cancer and describes how intravital imaging can help to understand the role of the tumour microenvironment in cancer progression and metastasis, and to develop novel treatments and therapies.

The activation of DNA damage tolerance (DDT) pathways as part of the replication stress response to DNA damage is key for maintaining genome integrity and, as a result, these pathways are closely linked to tumorigenesis. In this Review, Cybulla and Vindigni discuss the many connections between DDT, replication stress and cancer, detail opportunities for clinical biomarker development, and outline therapeutic strategies for targeting these pathways.

Three-dimensional bioprinted cancer models could revolutionize understanding and treatment of cancer. Neufeld, Yeini and Pozzi discuss how such models can reveal novel biomarkers and drug targets, illuminate mechanisms of tumorigenesis and interactions between tumour, stromal and immune cells, and advance personalized cancer therapy.

‘Ductal carcinoma in situ’ (DCIS) describes abnormal cells in the milk ducts. DCIS is often non-invasive, although a small proportion of cases leave the ducts and progress to invasive breast cancer. This Review discusses the existing data for distinguishing progressive and non-progressive DCIS, with a focus on informing current disease management strategies.

Clinical trials of immunotherapies have so far failed to demonstrate efficacy in high-grade serous ovarian cancers. Here, Kandalaft et al. classify high-grade serous ovarian cancers into distinct immunophenotypes that might account for these failures and could also provide a rational basis for tailored immunotherapy in the future.

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.

This Review describes how advances in lentiviral-based cellular barcoding techniques, including both genetic and optical barcoding, have enabled the spatiotemporal fate of individual cancer cells and their progeny to be tracked, providing valuable information for biological discovery and possible clinical translation.

This review gives an overview of natural killer (NK) cell-based immunotherapies. The authors describe the various engineering strategies used to increase NK cell cytotoxicity and persistence, as well as the current challenges and opportunities for the future design of next-generation NK cell therapies.

Environmental exposure to aristolochic acid-containing plant material and its use in traditional medicines have been linked to a wide range of cancers. In this Review, Das et al. describe the evidence for aristolochic acid as a potent carcinogen and explore the impact of public health measures on preventing aristolochic acid-linked cancers and nephropathy, with a call to action for the implementation of further preventative measures.