Resistance to therapy remains the biggest challenge to achieving cures in patients with cancer. In this Roadmap, Russo et al. overview the field of cancer drug-tolerant persister cells providing paths to advance our understanding of their biology with innovative technologies and recommend strategies to therapeutically target them to ensure that more prolonged responses are achieved in patients with cancer.

In this Expert Recommendation, Faupel-Badger and colleagues present a conceptual framework to define precancer and advance our understanding of the earliest changes that occur in the progression to overt cancer, providing novel opportunities to intervene to prevent or treat their emergence.

Large biobank projects such as FinnGen have enabled systematic searches for inherited factors that causally influence a wide range of human traits, including cancer risk and outcome. These explorations provide genetic insights for various aspects of cancer research, including improved risk prediction, enhanced biomarker and drug target discovery, and personalized medicine.

In a recent study published in Nature Genetics, Kübler, Nardone et al. analysed the mechanisms underlying tamoxifen-associated uterine cancer and identified PI3K pathway activation as a key non-genetic driver.

Urine-based tumour DNA detection enables non-invasive profiling of urological malignancies and may inform on distant cancers via trans-renal cell-free DNA (cfDNA). Here the authors propose the ‘minimal urine methods in experiments’ (MUMIE) framework to enhance validation and standardization of urinary cfDNA biomarkers.

In this Journal Club, Lopez-Hernandez and Ortega-Del Vecchyo discuss a study that mapped the genetic basis of hybrid incompatibility in swordtail fish, revealing melanoma-causing gene interactions that reduce survival in natural hybrid populations.

The outcomes for patients with cancer of unknown primary have improved through the use of molecularly guided therapies, for those both with and without a presumptive tissue-of-origin diagnosis. Genomic testing followed by molecularly guided therapies significantly improves survival compared to empiric chemotherapy, highlighting its practice-changing potential.

This Focus issue highlights current research at the intersection of ageing and cancer, and explores how insights gained from this may lead to better cancer prevention strategies and diagnostics, enhanced therapeutic efficacy and improvements to both patient quality of life and outcomes.