Review Articles

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.

In this Review, Meier et al. discuss the molecular mechanisms of necroptosis, delineate how this form of immunogenic cell death activates antitumour immune responses and explore the opportunities and limitations of targeting necroptosis for anticancer therapy.

This Review provides an overview of the complexity and significance of protein lipidation in cancer, outlines how targeting protein lipidation pathways offer promising avenues for developing cancer treatments, and discusses the current state of drugs targeting these pathways.

Extrachromosomal DNA (ecDNA) is now accepted as a major contributor to cancer pathogenesis. In this Review, Yan, Mischel and Chang highlight the recent advancements in ecDNA research, providing new insights into the biogenesis and maintenance of ecDNA, as well as its role in altering gene expression and promoting tumour heterogeneity.

In their Review article, Fuchs and colleagues discuss how a single or a few mutations in adult cells can lead to invasive cancers without a high mutational burden, demonstrating that non-genetic factors induce the epigenetic changes necessary for tumorigenesis.

In this Review, de Souza et al. discuss how advances in the ability to image protein markers at high-plex, at single-cell and even subcellular resolution, are expanding our understanding of tumour biology and clinical outcomes, and outline the future promise of combining such multiplex protein imaging methods with other forms of spatial omics.

Although p53 was once considered undruggable, in this Review, Peuget et al. discuss the progress made in targeting p53 as a form of cancer therapy with approaches ranging from restoration of mutant p53 function to inhibition of the negative regulator of p53, MDM2, as well as newer strategies, including p53-based mRNA vaccines and antibodies.

Transposable elements, also known as junk DNA, constitute nearly half of the human genome. This Review by Liang et al. discusses how tumours exploit these transposable elements during their evolution but also how they represent a vulnerability that could be targeted through immunotherapeutic approaches.

Although hyperactivation of BRAF has been well-established to drive tumour progression and drug resistance, the role of CRAF in cancer is becoming increasingly relevant. Here, Riaud et al. summarize the various oncogenic roles of CRAF and the potential for CRAF-targeted therapies to improve the clinical outcome for RAF1 altered tumours.

In this Review, Sato and colleagues provide an overview of the clinicopathological and phenotypical impact of lineage commitment and plasticity during tumorigenesis and progression of human epithelial cancer and discuss the molecular mechanisms that underlie histological lineage transition.

In this Review, Mempel et al. use our understanding of the physiological response programmes of the immune system to the more commonplace challenges it encounters as a framework to interpret observations of chemokine function in tumours. When viewed in this way, the design of more effective therapeutic interventions leveraging the chemokine system to recalibrate response patterns to cancer might be possible.

Numerous immunomodulatory antibodies for cancer treatment have been developed following the discovery of negative regulators of antitumour immunity such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4). The efficacy of these antibodies is determined not only by their ability to block or engage their target but also by their interactions with Fcγ receptors (FcγRs). This Review outlines our current knowledge of these interactions and discusses how we can use this knowledge to generate more effective cancer immunotherapies in the future.

Targeting platelets represents a promising approach to improve the therapeutic efficacy of chemotherapy and cancer immunotherapy. Here, Li and colleagues highlight the dynamic role of platelets in tumour development, progression, and response to therapy, and underscore the utility of tumour-educated platelets for precise tumour diagnosis and treatment.

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.