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.

Sex differences impact various non-reproductive organ cancers, often leading to higher cancer incidence and poorer outcomes in male individuals. In this Perspective article, Xiao, Lee et al. outline the biological factors contributing to sex bias in immuno-oncology, emphasizing the need for future research to offer a fuller understanding of sex disparities in cancer.

In a recent study published in Cell, Chhabra et al. identify age- and sex-dependent changes in skin fibroblasts that drive melanoma aggressiveness, with aged male fibroblasts promoting a slow-cycling, invasive state and resistance to targeted therapy in melanoma cells.

Chibaya, DeMarco et al. investigated a combinatorial approach of delivering innate immune agonists and RAS pathway-targeted therapies to remodel the tumour microenvironment and improve PDAC drug response.

In this Comment, Connor et al. discuss how the continued poor clinical translatability of preclinical studies highlights the need to mandate well-characterized models, ideally established in the orthotopic setting and, where feasible, treated with classical standard-of-care regimens.

Ciwinska et al. asked whether natural tissue remodelling can drive mutant cell expansion and identified three protective mechanisms in the healthy mouse mammary gland that constrain the ability of mutant cells to transform and give rise to cancer.

CRISPR screens in cell cultures reveal cancer dependencies yet often miss the metabolic nuances of tissues. In this Comment, Zuber and Palm highlight how modelling tumour-specific metabolic conditions can enhance our understanding of cancer biology and improve therapeutic discovery.

In this Tools of the Trade article, Xinwen Liu describes the development of VIBRANT, a vibrational spectroscopy method for high-content phenotypic profiling, and highlights its use to predict drug mechanisms of action or identify potential drug candidates.