Reviews & Analysis

This Review by Elena B. Pasquale outlines the current understanding of Eph receptor–ephrin signalling mechanisms in cancer progression and therapy resistance, and also details therapeutic strategies for targeting the Eph system as a novel cancer therapy and for improving the efficacy of conventional cancer therapies.

Deubiquitinating enzymes (DUBs) function in opposition to E3 ubiquitin ligases by removing ubiquitin from substrates to control protein and organelle homeostasis and responses to cellular stimuli. In this Review, Dewson et al. describe the many associations of DUBs with the hallmarks of cancer, with a view to identifying those DUBs most likely to impact cancer-associated phenotypes if targeted with selective inhibition.

Although tumour metabolism is well recognized as a key feature in cancer initiation and progression, little is known about metabolic reprogramming in patients. In this Review, Bartman et al. discuss stable-isotope tracing as a means to probe tumour metabolism in vivo and provide an overview of isotope labelling studies performed in patients with cancer.

In this Review, Swietach and colleagues discuss how the pH balance is dysregulated in tumours and how alterations in intracellular and extracellular pH affect tumour biology to accelerate disease progression, providing a rationale for therapeutic targeting of acid–base disturbances in cancer.

Adrenocortical carcinoma is a rare endocrine cancer with a dismal survival rate and limited therapeutic options. This Review outlines the recent advances that have been made in the understanding of the molecular basis of adrenocortical carcinoma and what this means for the diagnosis and treatment of patients with this cancer type.

T cells can acquire a broad spectrum of differentiation states following activation; certain subtypes of T cells have emerged as key determinants of cancer immunity and response to immunotherapies. Here, Gebhardt, Park and Parish discuss the phenotypic and functional variation of stem-like exhausted CD8⁺ T cells and memory CD8⁺ T cells, and how it contributes to their roles in immune escape and cancer outcome.

Transfer RNAs have long been known as static adaptors that translate the genetic code but are now emerging as dynamic regulators in health and disease, including cancer. This Review discusses how the deregulation of the tRNA pool, tRNA-derived small RNAs and tRNA synthetases impacts tumour initiation and progression.

This Review summarizes how the structural details that were revealed by cryo-electron microscopy and X-ray crystallography and insights into molecular basis of polyspecificity and mechanistic studies shaped the understanding of the role of ATP-binding cassette transporter in cancer multidrug resistance, culminating in new therapeutic approaches to sensitize multidrug-resistant cancer cells to conventional and targeted therapies.

Live-cell imaging can provide spatial, morphological and molecular understanding of cancer response to treatment. Here, Alieva et al. review its recent application for uncovering drug mode of action and tumour heterogeneity in response to treatment and discuss its application for next-generation precision medicine.

Sex steroids are major promoters of the growth of breast and prostate cancers. This Review by Poutanen et al. describes the development of treatments for these cancer types that act to restrict sex steroid availability for receptor binding by inhibiting steroid biosynthesis, being a complementary mechanism of action to the more traditional sex steroid antagonists.

This Review discusses the impact of steroid-receptor-mediated modifications of long-range chromatin interactions on transcriptional heterogeneity and the initiation, progression and therapy response of hormone-dependent cancers.

Although selective antagonism of oestrogen receptor signalling in breast cancer has been one of the most successful therapeutic approaches in oncology, resistance is a major clinical challenge. In this Review, Will et al. explore mechanisms of oestrogen-receptor-α-targeted therapeutic resistance and strategies to overcome it.

Understanding how cell intrinsic and extrinsic factors combine to initiate transformation holds promise for the development of strategies to prevent, detect and treat cancer early. In this Review, Jassim et al. outline the various theories that have currently been proposed for cancer origins, and the determinants of cancer risk upon which they are based.

Since the advent of genome-wide association studies, thousands of common alleles have been linked with the risk of cancer. Here, Yang et al. review the development, utility and predictive power of polygenic risk scores and the ongoing debate about their potential for clinical application in cancer.

In this Review, Fagin et al. outline the oncogenic drivers of the common endocrine tumours, which derive from thyroid follicular cells, and how these impact tumour phenotypes and disease progression.

The role of the microbiota in tumorigenesis has garnered considerable attention over the past two decades. In this Review, El Tekle and Garrett explore the current and evolving understanding of microbiota in cancers of various internal organs, as well as highlighting opportunities for targeting bacteria for cancer prevention, diagnostics and treatment.

Tumour ecosystems encompass a multitude of variables, including enzymatic, metabolic and immune components within the tumour and across organs. This Review summarizes how micro-engineering approaches and nanosensors have been used to establish multicomponent tumour models and to assess tumour plasticity.

In this Review, Zeng et al. describe the recent single-cell omics studies that have revealed the heterogeneity of human tumour endothelial cells and demonstrate that the phenotypes of these cells extend beyond that of simply being angiogenic, an observation that could be translated into the clinic to improve upon the success rate of current anti-angiogenic therapies.

mRNA for therapeutics is growing in popularity owing to the relative ease of synthesis and nucleotide alteration for personalized medicine. In this Review, Liu et al. outline the characteristics of in vitro transcribed mRNA-based therapeutics for cancer treatment, highlighting the ongoing clinical studies, current challenges and future opportunities.

The activities of YAP and TAZ have long been associated with cancer progression. In this Review, Franklin et al. provide an integrated perspective on the latest understandings of YAP and TAZ activation, including their role as a tumour suppressor, as well as advances in YAP and TAZ therapeutic treatments.