The decision to centre emerging investigators rather than established luminaries is itself a statement about how science should evolve. The authors argue that researchers early in their careers are uniquely positioned to challenge prevailing assumptions, adopt interdisciplinary approaches and redirect priorities that may have calcified over decades. The resulting collection of perspectives spans an unusually wide technical range, from neoadjuvant immunotherapy in colorectal cancer to somatic mosaicism in healthy tissues, from the nervous system’s role in tumour progression to artificial intelligence models that predict cellular responses to genetic perturbation. Together, the six contributions sketch a research agenda that is more integrated, more prevention-focused and more computationally ambitious than anything the field has attempted before.

One thread running through the article is the remarkable maturation of cancer immunotherapy, particularly when treatment is moved earlier in the disease course. Myriam Chalabi, a medical oncologist and physician scientist at the Netherlands Cancer Institute in Amsterdam, has built her research programme around immunotherapy delivered in the neoadjuvant setting, using novel treatment combinations within innovative trial designs. The clinical evidence underpinning this shift is striking: recent work has demonstrated neoadjuvant immunotherapy in mismatch-repair-proficient colon cancers, while separate research has shown that non-operative management of mismatch repair deficient tumours can produce durable responses, in some cases allowing patients with rectal cancer to avoid surgery entirely. These results suggest that the immune system, when engaged before a tumour has been removed, can eliminate disease that conventional staging would consider established, and they raise the prospect of organ-preserving treatment as a realistic goal rather than an aspirational one.

Yet immunotherapy has also exposed the limits of tumour-centric thinking, and several of the authors argue that the next 25 years must focus on the host as much as the tumour. James L. Reading, an associate professor of cancer immunology at UCL who leads the Pre-cancer Immunology Laboratory, studies T cell-driven cancer interception — the idea of detecting and eliminating tumours before they become clinically invasive. His work builds on the discovery that reservoirs of stem-like CD8-positive T cells in tumour-draining lymph nodes sustain ongoing antitumor immune responses, and that conventional type I dendritic cells maintain pools of proliferative, tumour-antigen-specific TCF1-positive CD8-positive T cells in those same nodes. Understanding how these immune reservoirs are established and maintained during pre-invasive disease, he argues, could transform early detection from passive imaging into active, immune-guided interception, catching malignancy at a stage when cure rates approach certainty.

The genomic dimension of this preventive agenda is developed most fully by Tim H. H. Coorens, a group leader at the European Bioinformatics Institute who studies how somatic mutations accumulate in normal cells. Twenty-five years ago, cancer genomes were largely studied in isolation from the tissues that produced them. Today, it is clear that essentially every cell in the body accrues mutations over a lifetime, and that clones of mutant cells — some harmless, some pre-malignant — expand and compete in otherwise healthy tissue. Coorens contributed to the Somatic Mosaicism Across Human Tissues network, an effort to catalogue this variation systematically, and recent analyses have shown that age itself can distinguish selective clonal expansion from simple mutational causation in cancer genomes. Meanwhile, the real-world clinical utility of tumour whole-genome sequencing in solid cancers has now been demonstrated at scale, suggesting that comprehensive genomic profiling is moving from research luxury to standard of care. The conceptual shift is profound: cancer becomes not a foreign invader but one possible endpoint of a lifelong evolutionary process, and the levers for prevention may lie in the dynamics of normal tissue.

Perhaps the most visually striking frontier is cancer neuroscience. Leanne Li, a group leader at the Francis Crick Institute in London, combines cancer genetics with neurotechnologies to decipher the logic of interactions between tumours and the nervous system in mouse models. The field’s roots reach back more than a century to observations of nerves within tumours made using methylene blue vital staining, but modern cancer neuroscience has exploded in the past decade. Recent single-neuron sequencing has revealed how individual neurons are reprogrammed by pancreatic cancer, and comprehensive reviews have mapped the past, present and future of the discipline. Li also leads InteroCANCEption, a multidisciplinary team funded by Cancer Grand Challenges to tackle the broader question of how interoception — the body’s sensing and regulation of its own internal signals, a concept elaborated in modern neuroscience — shapes tumour initiation, growth and response to therapy. If tumours co-opt neural circuitry the way they co-opt blood vessels, then neuromodulatory drugs already approved for other conditions could become unexpected additions to the oncology arsenal.

Resistance to therapy, the stubborn core of cancer mortality, is the focus of Shensi Shen, associate professor at West China Hospital, Sichuan University. His work centres on drug-tolerant persister cells — a subpopulation of cancer cells that survives initial treatment not through genetic mutation but through reversible shifts in cell state. Reviews have traced the journey of persister cell biology from basic questions to clinical opportunities, and single-cell analyses have shown that genetically homogeneous cancer cells can diverge into multiple distinct clonal fates when exposed to the same drug. Shen’s particular interest is in layered translational control: the regulation of how messenger RNA is decoded into protein, which allows cancer cells to deploy hidden protein functions and switch states under therapeutic pressure. Because these transitions are non-genetic, they are also potentially reversible, which makes the persister state an attractive target for combination strategies designed to block the escape routes that tumours use to survive targeted therapy and immunotherapy alike.

Underpinning all of these biological questions is a computational revolution, examined by Ewa Szczurek, associate professor at the University of Warsaw and director of the Institute of AI for Health at Helmholtz Munich. Szczurek develops artificial intelligence models for molecular biology and medicine, and her perspective is notably sober about the current state of the field. While foundation models promise to predict how cells respond to genetic and pharmacological perturbations — an ambition exemplified by recent preprint work on state-based prediction of cellular responses — independent evaluations have shown that deep-learning-based gene perturbation effect prediction does not yet outperform simple linear baselines in many settings. Her message is that the next 25 years of AI in cancer research will be defined not by model size but by data quality, experimental validation and careful benchmarking. If the field heeds that warning, machine learning could genuinely accelerate target discovery and personalised treatment; if it does not, hype risks outrunning biology.

Woven together, the six perspectives describe a field in mid-revolution. The tumour-as-isolated-entity model is giving way to a systems view in which cancer is embedded in the evolutionary dynamics of normal tissues, the immune landscape of pre-invasive disease, the neural circuitry of the host body and the non-genetic plasticity of individual cells. Clinical paradigms are shifting in parallel: treatment is moving earlier, surgery is sometimes becoming optional, and molecular residual disease monitoring — exemplified by analyses of adjuvant osimertinib in resected EGFR-mutated lung cancer — is becoming a guide for post-operative decisions. The anniversary article also translates premalignant biology into strategies for intercepting non-small-cell lung cancer, illustrating how laboratory insight can be converted directly into prevention trials.

What emerges most clearly is a demand for interdisciplinarity as a structural principle rather than a slogan. The authors themselves embody it: a clinician designing immunotherapy trials, a bioinformatician decoding mutation accumulation, a neuroscientist engineering tools to interrogate tumour-nerve crosstalk, an immunologist chasing T cells before invasion, a molecular biologist tracking protein-level resistance and a computer scientist stress-testing the field’s newest models. Their collective wager is that the major killers of the next quarter-century will not be defeated by any single breakthrough but by the deliberate integration of genomics, immunology, neuroscience, developmental biology and computation — and by the willingness of a new generation to ask questions their predecessors did not think to ask.

Subject of Research: Emerging investigators' perspectives on the future priorities of cancer research over the next 25 years

Article Title: The next 25 years of cancer research: emerging perspectives and priorities

Article References: Chalabi, M., Coorens, T. H. H., Li, L., Reading, J. L., Shen, S., & Szczurek, E. (2026). The next 25 years of cancer research: emerging perspectives and priorities. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00975-3

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00975-3

Keywords: cancer research, Nature Reviews Cancer, immunotherapy, neoadjuvant therapy, somatic mosaicism, cancer neuroscience, cancer interception, drug-tolerant persister cells, tumour heterogeneity, whole-genome sequencing, artificial intelligence, early detection

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