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.

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.

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.

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 this Perspective, Cambria et al. propose that mechanical cues within the primary tumour that are known to promote metastasis imprint a persistent phenotype on cancer cells through mechanical memory to further facilitate cancer metastasis at distant sites.

In this Perspective article, Mel Greaves and co-workers outline emerging evidence that suggests that children with newly diagnosed acute lymphoblastic leukaemia may have a delayed maturation of the gut microbiome compared with healthy children, a deficit that might be associated with early-life epidemiological factors and could contribute to the risk of transformation of preleukaemic clones in response to common infectious triggers.

In this Perspective, the authors suggest that different tumour microenvironments have ‘archetypal’ qualities across all cancers — characteristic and repeating collections of cells and gene-expression profiles at the level of the bulk tumour. They propose the existence of 12 dominant immune archetypes.

Eukaryotic initiation factor 4F (eIF4F) controls the translation of a subset of transcripts that include those encoding oncogenic proteins. In this Perspective article, Bartish et al. discuss the implications of targeting eIF4F on immune and stromal cells in the tumour microenvironment. In addition to discussing data from cancer models, the authors incorporate extensive data from non-cancer contexts to identify potential desirable or unwanted effects of eIF4F inhibition in these cells.

In this Perspective, Magnon and Hondermarck introduce the emerging field of cancer neuroscience and outline how the bidirectional crosstalk between the brain and peripheral tumours drives cancer development and progression.

Fibrolamellar hepatocellular carcinoma is a rare cancer type and, as such, research into this disease comes with many challenges. In this Perspective, Sanford Simon tells of his personal journey and experiences in the fight against this rare cancer type.

In this Perspective, Tsoumakidou explores the emerging role of cancer-associated fibroblasts as positive regulators of the adaptive immune system in cancer.

Clinical correlative data and a plethora of preclinical studies of cancers have shown that both tumour-associated and metastasis-associated macrophages play an important role in promoting cancer. In this Perspective article, Cassetta and Pollard chronologically explore the evolution of our understanding of tumour-associated macrophage biology and enabling technologies.

In this Perspective, Wahida et al. consider six riddles in precision oncology that must be solved to achieve better clinical responses to molecular targeted therapies.

The gut microbiota has been shown to regulate responses to various cancer therapies, and the microbial species involved and their underlying mechanisms have begun to be unravelled. In this Perspective, Fernandes and colleagues present this evidence and then outline how it could be used to develop microbiota-based therapies for patients with cancer.

This Perspective outlines the preclinical emergence of smart cell therapeutics, which when paired with machine learning analysis of genomic data could be implemented in the clinic to both enhance tumour recognition and prevent tumour escape.

Malignant cells show uninhibited proliferation and cellular plasticity, features also reminiscent of embryogenesis. In this Perspective, Sharma and colleagues present their oncofetal ecosystem concept, discuss evidence of oncofetal reprogramming in malignant and non-malignant cells, and debate the therapeutic relevance of these findings.

Structural variations (SVs), which comprise genome-level aneuploidies and rearrangements, result in both copy number changes and novel interactions between formerly distant genomic elements. This Perspective discusses how the folding of the 3D genome, and differences in its folding across cell types, affect the formation of SVs and their impact on cancer cell fitness in different cancer types.

This Perspective discusses the role of multicellular tumour networks, formed by tumour microtubes and tunnelling nanotubes, in brain tumours. It also discusses their relevance to therapy resistance and how these networks might be therapeutically targeted, and their potential relevance in other cancer types.

This Perspective discusses how polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.

Liquid–liquid phase separation (LLPS) has been revealed as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells. This Perspective discusses how LLPS shapes the biochemical landscape of cancer cells, providing insight into emerging findings of dysregulated LLPS promoting cancer pathology.