The single most transformative technical development of the period is widely agreed to be the sequencing revolution. The landmark 2005 demonstration of genome sequencing in microfabricated high-density picolitre reactors opened the door to reading tumour genomes at scale, an advance that would have been unimaginable when the journal launched. From that technological foundation flowed the systematic discovery of cancer genes, the classification of tumours by their mutational signatures and the rise of precision oncology as a clinical discipline. The identification of recurrent mutations of the BRAF gene in human cancer in 2002, before the sequencing revolution fully matured, had already signalled what was to come: single genetic lesions, once found, could define entire treatment strategies.

Clinical actionability has expanded at a remarkable pace. Analyses quantifying the expanding landscape of clinical actionability for patients with cancer show that a steadily growing fraction of tumours now harbour alterations for which targeted drugs or guided treatment decisions exist. The poster child of this era remains BRAF V600E inhibition in melanoma, but the paradigm has matured in sophistication. When colon cancers proved unexpectedly unresponsive to BRAF inhibition, researchers discovered that feedback activation of EGFR was protecting the cells—a finding that led directly to the FDA-approved combination of BRAF and EGFR inhibitors for BRAF-mutant colorectal cancer, a therapy developed in René Bernards’ laboratory at the Netherlands Cancer Institute. The lesson embedded in that story reshaped the field: cancers are wired for resilience, and single-agent thinking is rarely sufficient.

That lesson now drives the logic of synthetic lethality, one of the most productive conceptual frameworks of the past decade. Rather than attacking oncogenes directly, synthetic lethal strategies exploit vulnerabilities created by a tumour’s alterations. A striking recent example is the demonstration that amplification of the cyclin E1 gene CCNE1, common in aggressive ovarian and other cancers, creates a dependence on the PKMYT1 kinase that can be pharmacologically exploited. This approach extends druggability into territory long considered untouchable, and drug discovery scientist Paul Workman of the Institute of Cancer Research has championed the broader project of drugging the cancer genome—developing chemical inhibitors and small-molecule research tools against targets once dismissed as intractable.

Perhaps no target symbolises both the promise and the frustration of the era better than RAS. Mutant RAS genes were identified in the early 1980s and were long considered undruggable, a verdict repeated in reviews for decades. Yet the past few years have delivered direct RAS inhibitors, and a 2026 phase three trial reported that the RAS inhibitor daraxonrasib outperformed chemotherapy in previously treated metastatic pancreatic cancer—one of the most difficult malignancies to treat. Allan Balmain, whose laboratory uses mouse models to trace the cells that acquire initiating oncogenic mutations, notes that interpreting such advances requires a deeper understanding of tumour evolution itself: when a mutation arises, in which cell it arises, and what environmental forces promote or suppress its expansion.

That evolutionary perspective has been genuinely subversive. Sequencing of normal human skin revealed a high burden of somatic mutations and pervasive positive selection operating in histologically normal tissue—mutant clones competing for space in organs that look entirely healthy. Even more provocative, work in mosaic mouse skin has shown that injury can prevent the expansion of Ras-mutant cells, overturning the intuitive assumption that wounding uniformly promotes carcinogenesis. Complementing this, chemically induced skin tumours have been traced to long-lived stem cells of the upper hair follicle, underscoring that the identity of the cell of origin is a decisive variable in tumour outcome. Cancer, in this view, is not simply a cell-autonomous genetic disease but an ecological process embedded in tissue dynamics, environmental exposure and time.

The cancer stem cell concept illustrates how an important idea can be discovered, oversimplified and then properly understood only over decades. The founding observation—that human acute myeloid leukemia is organized as a hierarchy originating from a primitive hematopoietic cell—was published in 1997, before the review period began. The intervening years saw the concept generalized, contested and eventually refined. As Hans Clevers and Eduard Batlle argued in revisiting the field, functional stemness depends on cellular context and state rather than immutable identity, and epithelial cell plasticity allows cells to cross lineage boundaries that once seemed fixed. The modern synthesis holds that many tumour cells can transiently adopt stem-like behaviour, which has important consequences for therapy resistance and relapse, even if the simplest hierarchical models proved too rigid.

Technology has also reshaped how tumours are studied. Clevers’ pioneering work on organoids—self-organizing, three-dimensional cultures derived from adult stem cells—created patient-derived models that preserve the genetic and functional features of the original tissue, bridging the long-standing gap between cell lines and patients. Organoid biobanks now support drug screening, gene-function studies and personalised treatment predictions, and the technology has been commercialised widely, with Clevers holding patents and co-founding companies in the field. Alongside organoids, powerful tools such as CRISPR-based functional genomics, exemplified by the synthetic lethality screens of the Bernards laboratory, allow systematic interrogation of cancer vulnerabilities directly in human cells.

Beyond genes, the anniversary reflections give substantial weight to metabolism and the tumour microenvironment, areas that were marginal when the journal began but are now central. Tumour-derived lactic acid was shown to functionally polarise tumour-associated macrophages, demonstrating that a metabolic by-product can reprogram immune cells within the microenvironment. Cancer-associated cachexia, the devastating wasting syndrome that contributes to a large fraction of cancer deaths, has recently been connected to mechanistic insight in human studies, replacing decades of descriptive work. Karen H. Vousden, whose research spans p53 biology and metabolism, has explored how dietary composition interacts with tumour metabolism, and precision nutrition companies are now testing whether manipulating non-essential amino acids can enhance therapy in patients. The message is that cancer cannot be understood as a tumour in isolation; it is a systemic disease reshaping the entire body.

The newest force transforming the field is artificial intelligence. The transformer architecture described in ‘Attention is all you need’ underpins models that now predict biomolecular interactions with remarkable accuracy, as demonstrated by AlphaFold 3, and AI agents are being designed to empower biomedical discovery end to end—from hypothesis generation to experimental execution. Marinka Zitnik of Harvard Medical School leads work on multimodal and agentic AI systems paired directly with laboratory experiments, and is team lead of AURORA within Cancer Grand Challenges. The authors’ cautious optimism is tempered by experience: past waves of overhyped technologies promised more than they delivered, and AI will need to demonstrate genuine predictive power in clinics, not only impressive benchmarks, to transform outcomes.

Woven through the reflections is an honest accounting of unmet expectations. Not every large-scale endeavour—from indiscriminate high-throughput screening to simplistic gene-expression signatures—delivered what early enthusiasts forecast. Combination therapy remains difficult to develop because toxicity, not efficacy, is usually the limiting factor. Drug resistance evolves faster than new drugs arrive, and late-stage solid tumours continue to claim most of the lives that cancer kills. Yet the trajectory is unmistakable: five-year survival has risen for many malignancies, targeted combinations have turned once-fatal diseases into chronic or curable conditions, and the mechanistic depth of the field is unrecognisable compared with 2001. The authors’ shared conclusion is that the next 25 years will be judged by how well the field integrates these hard-won insights—evolutionary, ecological, metabolic and computational—into treatments that reach every patient, not just those with actionable mutations in privileged tumour types.

Subject of Research: A 25-year retrospective on transformative advances and unmet expectations in cancer research

Article Title: Reflecting on 25 years of cancer research: transformative advances and unmet expectations

Article References: Balmain, A., Bernards, R., Clevers, H., Vousden, K. H., Workman, P., & Zitnik, M. (2026). Reflecting on 25 years of cancer research: transformative advances and unmet expectations. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00974-4

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00974-4

Keywords: cancer research, Nature Reviews Cancer, tumour evolution, precision oncology, synthetic lethality, RAS inhibitors, cancer stem cells, organoids, tumour metabolism, cachexia, artificial intelligence, drug discovery