Perspectives

In this Perspective, de Magalhães explores the evolutionary relationship between cancer and ageing, proposing that the need to minimize cancer risk early in life may contribute to tissue degeneration later on, representing a trade-off that constrains the evolution of longer lifespans.

Allogeneic haematopoietic stem cell transplantation remains the cornerstone of curative treatment for advanced myeloid malignancies. In this Perspective, Foldvari et al. propose that T cells engineered to express tumour-reactive T cell receptors (TCRs) may offer a safer and more effective alternative. They outline key considerations for identifying and validating suitable target antigens and matching TCRs, and for advancing these therapies towards clinical application.

In this Perspective, Lazure and Gomes argue that metabolic changes that occur as a result of ageing may shape tumour initiation and progression and the development of metastatic disease.

Comparative oncology combines evolutionary biology, ecology, veterinary medicine and clinical oncology to better understand cancer, for example, by identifying the molecular and cellular mechanisms underlying the remarkable cancer resistance of some taxa. Therefore, this Perspective by Vincze et al. calls for the increased use of non-conventional model organisms in cancer research to advance cancer prevention and treatment strategies.

Transforming growth factor-β (TGFβ) has a well-established role in malignancy and its inhibition has demonstrated strong preclinical activity. However, TGFβ blockade has repeatedly failed in clinical trials. Here, Barcellos-Hoff and Yom utilize human papillomavirus (HPV)-driven cancer as a model to explain these discrepancies and emphasize the need for refined strategies and understanding of TGFβ signalling to enhance therapeutic efficacy.

In this Perspective, Joshua Rubin emphasizes the importance of gender–sex interaction (GSI) differences in cancer biology and clinical parameters to enhance precision medicine. He outlines the challenges and opportunities of integrating GSI effects into personalized oncology and argues that optimal outcomes require extending our current molecular approaches to include family history, life history and individual vulnerabilities in our diverse groups of patients with cancer.

In this Perspective, Kamila Naxerova discusses how genetic analyses of primary tumours and matched metastases can distinguish between competing metastasis evolution models, arguing that further insights into human metastasis biology could be enabled by a framework that rigorously quantifies whether metastases descend from a nonrandom selection of primary tumour lineages.

Conventional chemotherapy has successfully cured millions of patients with cancer, yet the mechanisms of action for this remain unclear. In this Perspective, Letai and de The assess the existing mechanisms proposed for the success of chemotherapy, identify gaps in our understanding and suggest principles for improving the utility of conventional chemotherapy to enhance treatment efficacy.

The Cancer Dependency Map (DepMap) is a data repository and research platform that can be utilized to systematically identify cancer vulnerabilities. Here Arafeh, Shibue et al. outline the current limitations and future strategies to enhance the DepMap project.

Efficient clinical trials are crucial for advancing cancer care. In this Perspective, the authors propose a platform that leverages circulating tumour DNA to identify patients with early-stage cancer at high risk of recurrence and enrol them onto therapeutic clinical trials. This approach would enable faster, smaller trials and streamline evaluation of drugs aimed at preventing disease recurrence and increasing cure.

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.