Oncolytic virotherapy has evolved from a platform predicated on lysis of cancer cells into a sophisticated system for intratumoural immune reprogramming; the prevailing 'cold-to-hot' paradigm captures only part of this potential. A fundamental limitation shared by immune checkpoint inhibitors (ICIs) and early-generation oncolytic viruses (OVs) is a reliance on pre-existing tumour-specific T cells (TSTs), which presents an immunological ceiling that constrains antitumour activity - given that these agents have a limited capacity to generate TSTs de novo. Next-generation OVs overcome this constraint by functioning as agents for antigen-agnostic in situ cancer vaccination: intratumoural infection triggers immunogenic cell death, releasing potentially the full cancer proteome under pathogen-associated and/or damage-associated molecular pattern adjuvant conditions, thereby driving T cell priming against patient-specific neoantigens. In this Perspective, we delineate four pillars for the development of next-generation OVs. First, intratumoural vaccination as immunological ignition, with initial clinical data demonstrating T cell clonotype broadening, abscopal tumour regression and survival benefit in patients with ICI-refractory disease. Second, optimized payload-driven immune priming to hyperactivate antigen-presenting cells. Third, revised efficacy evaluation and end points using response criteria as well as novel biological correlates that better capture delayed and abscopal immune-mediated tumour control. Fourth, OV as the foundational immuno-oncology platform: according to the 'triple-A' framework encompassing admission, availability and activation of TSTs, next-generation, payload-engineered OVs uniquely satisfy all prerequisites for antitumour immunity simultaneously, with evidence from clinical trials of such agents supporting an 'OV-prime, ICI-amplify' strategy. Notably, OVs are systemic immune-reprogramming platforms that are delivered locally, not local therapies with incidental systemic effects.
Glioblastomas remain the most lethal primary brain tumour in adults, with targeted therapies delivering only limited benefit despite deep molecular characterization. Several targeted drugs have received regulatory approval for low-grade gliomas, although progress in glioblastomas remains constrained by, among other aspects, extensive intratumoural heterogeneity, pathway redundancy, cellular plasticity and limited drug delivery to the central nervous system. Some of these challenges might be mitigated through strategies that enhance blood-brain penetration, including focused ultrasonography, convection-enhanced delivery, efflux avoidance and chemical modifications. Improved tumour profiling through multiregional sampling, prioritization of truncal dependencies and the development of novel therapeutic modalities, such as antibody-drug conjugates and theranostics, might also further improve outcomes. In this Review, we summarize the therapeutic landscape of targeted therapies in glioblastomas, spanning major target classes including receptor tyrosine kinases, intracellular signalling proteins, cell-cycle dysregulation and synthetic-lethal vulnerabilities. We also examine emerging strategies targeting genome integrity and telomeres, epigenetic modulators, and tumour-neural circuitry. Furthermore, we highlight tumour heterogeneity and extrachromosomal DNA dynamics as key drivers of oncogene amplification and therapeutic resistance as well as the roles of novel clinical trial designs and liquid biopsy-based monitoring strategies. Lastly, we discuss pathway-based glioblastoma classification and master kinase mapping as methods for aligning drugs with functional tumour states.
The phase III FIGHT-302 trial demonstrated that the FGFR inhibitor pemigatinib improves progression-free survival and response rates versus first-line chemotherapy in patients with advanced-stage FGFR2-rearranged cholangiocarcinoma. However, the trial accrued slowly and closed early after chemoimmunotherapy became the new standard of care. FIGHT-302, alongside two similarly terminated trials, highlights the need for innovative trial designs and flexible regulatory frameworks to evaluate therapies in rare, biomarker-defined populations.
PROTEUS met its amended co-primary end points but should not be interpreted as practice changing. The trial compared two experimental strategies rather than the current standard of care, relied on an unvalidated approach (prostate-specific membrane antigen-PET) for assessments of metastasis-free survival, demonstrated minimal absolute benefit with increased toxicity and lacks both mature overall survival data and sufficient data on patient-reported outcomes to support adoption.
Yue and colleagues present a landmark anatomical atlas of human protein abundance across non-malignant tissues and cancers. We argue that precision oncology needs functional proteomic maps that add signalling activity, post-translational modifications, pathology-guided compartment resolution, metastatic and longitudinal sampling, clinical annotation and population diversity to make proteomics therapeutically actionable.
Oncology clinical trials are often characterized by slow accrual, high failure rates and limited generalizability, reflecting both biological complexity and operational inefficiencies. Advances in artificial intelligence (AI) - enabled by large-scale electronic health record datasets and machine learning methods - offer new opportunities to address these challenges across the clinical trial lifecycle. In this Review, we discuss applications of AI across pre-trial design, trial conduct, and post-trial inference and generalization, highlighting how these tools can improve trial feasibility, support patient engagement and extend the relevance of trial findings. We also address cross-cutting challenges related to equity, data quality and drift, transparency, and regulatory oversight. The most immediate and evidence-supported role of AI in oncology trials lies in augmenting operational workflows under human oversight, particularly in the identification of candidate patients for enrollment, eligibility assessment, data extraction and trial monitoring (including remote patient and/or safety monitoring as well as monitoring of AI model performance and real-time trial data extraction) - applications that are now being implemented at select cancer centres. By contrast, AI applications designed to replace clinical evidence generation, such as synthetic control arms, outcome-prediction simulations and digital twins, remain at earlier stages of development, with limited prospective validation and unresolved methodological and regulatory challenges. Ultimately, we argue that achieving the potential of AI in oncology clinical trials will require rigorous prospective validation, harmonized regulatory standards, and coordination among clinicians, trialists, regulators, industry and patients.
Analysis of tissue biopsy samples is the gold-standard approach to cancer diagnosis and patient selection for biomarker-guided therapies. Although spatial analyses of tumour tissue can provide important insights into local antitumour immune responses, repeated tumour biopsy is invasive and rarely feasible for monitoring dynamic immune responses over time. Technical advances have enabled multimodal analyses of cells and cellular products in peripheral blood samples, which can be obtained easily and repeatedly over the course of the disease. These liquid biopsy-based approaches cannot provide spatial information on the tumour immune microenvironment and tumour-derived material can be highly diluted in the circulation, yet they offer a unique opportunity to monitor systemic immune dynamics, anticipate responses to immunotherapies and detect emerging resistance to treatment. Thus, blood-based analyses might complement tumour tissue analysis. In this Review, we discuss insights on systemic antitumour immune responses that can be gained through the analysis of tumour-derived biomarkers in peripheral blood and/or circulating immune cells.
Interim data from the phase III OptiTROP-Lung05 trial demonstrate that adding the TROP2-targeted antibody–drug conjugate sacituzumab tirumotecan to pembrolizumab improves progression-free survival in patients with PD-L1-positive advanced-stage non-small-cell lung cancer. Herein, I present several questions that need to be addressed before this combination can be considered a new standard of care, such as effect on overall survival, long-term safety, global generalizability and biomarker refinement.
Crossover in trials should not be viewed as confounding, but as informative. Crossover reveals whether deferring therapy produces outcomes comparable to those from earlier use. Statistical crossover-adjustment methods carry unaccounted biases and limited clinical utility. Crossover should instead guide treatment-sequencing decisions, weighing toxicity and cost against any overall survival benefit from earlier intervention.
Neoadjuvant chemoimmunotherapy, comprising an anti-PD-(L)1 antibody and platinum-doublet chemotherapy, given alone or as part of a perioperative regimen with the addition of adjuvant anti-PD-(L)1 therapy, has become the standard of care for patients with early-stage, resectable non-oncogene-driven non-small-cell lung cancer (NSCLC). This approach has demonstrated substantial increases in pathological response rates and improvements in long-term outcomes, including overall survival. However, these advances have largely been achieved through uniform treatment application across biologically heterogeneous tumours. As a result, a central challenge in contemporary perioperative management is how to identify which patients require escalation or de-escalation of treatment following surgery and which individuals could safely avoid unnecessary treatment. In this Review, we summarize current evidence supporting pathological response, and particularly pathological complete response (pCR), as a robust and clinically meaningful surrogate for durable benefit in patients with NSCLC. We then consider how complementary tools, including circulating tumour DNA, radiomics and metabolic imaging approaches, and baseline molecular and immune biomarkers, can be integrated to refine patient selection and dynamically adapt perioperative strategies. Finally, we describe potential therapeutic strategies to intensify perioperative treatment in biologically high-risk populations, with the dual objective of increasing the likelihood of a pCR and improving disease control in patients with an insufficient pathological response.
Modern oncology has built highly efficient pathways for patent-protected innovation, but no equivalent machinery for evaluating and developing promising off-patent therapeutics. Herein, we frame ‘open-source oncology’ as a parallel public-interest infrastructure to test, authorize and implement credible generic agents. Designed to translate ownerless evidence into standard-of-care treatments, this framework applies the same scientific seriousness devoted to proprietary drugs, decoupling clinical value from commercial ownership.
China accounts for nearly 17% of the global population yet contributes approximately 25% of the global cancer burden with >5 million new cancers diagnosed every year; this evolving landscape is reshaping the global pattern of cancer burden. Over the past decades, cancer epidemiology trends have substantially shifted in China. Driven by a rapidly ageing population and an expanded diagnostic capacity, the number of newly diagnosed cancers in China is rising rapidly and particularly of those that are most common in high-income countries, such as lung, colorectal, prostate, thyroid, female breast and cervical cancers. Conversely, the incidence of cancers historically prevalent in China, including oesophageal, gastric and liver cancers, has been declining substantially. In response to this escalating and evolving cancer burden, China has implemented a series of national cancer control initiatives starting in 1986. In this Review, we provide a comprehensive overview of the epidemiology and temporal trends of cancer burden in China, both overall and for the major cancer types, and analyse the key contributors to this landscape, including risk factors, screening programmes and cancer care provision. In the context of national cancer control policies and targets, we further assess progress and discuss the remaining challenges in prevention, screening and cancer treatment, as well as the implications for global cancer control in the coming decades.
Antibody-drug conjugates (ADCs) have transformed the cancer therapeutic landscape over the past two decades, profoundly shaping treatment outcomes across a wide array of indications. Three ADCs are currently approved for previously treated gynaecological cancers: mirvetuximab soravtansine for folate receptor-α-positive ovarian cancer, trastuzumab deruxtecan for solid tumours expressing HER2 (defined as a staining intensity on immunohistochemistry of 3+) and tisotumab vedotin for cervical cancer (independent of tissue factor expression). Current research priorities include identifying novel targets, better understanding mechanisms of resistance and sequencing strategies, and optimal management of the toxicities of ADCs. Moreover, rational combinations could reinforce and extend the clinical potential of these agents, as has already been demonstrated with the addition of ADCs to immune checkpoint inhibitors in an effort to amplify antitumour immunity and prolong the durability of clinical responses. In this Review, we provide an overview of the current landscape of ADCs in gynaecological malignancies, highlighting key advances and future opportunities.
The therapeutic landscape of platinum-resistant ovarian cancer is rapidly evolving, with recent phase III trials demonstrating, for the first time, meaningful overall survival improvements beyond bevacizumab-based therapy. Herein we discuss how trials such as MIRASOL and, more recently, ENGOT-ov65/KEYNOTE-B96 and GOG30173/ENGOT-ov72/ROSELLA have established new standards of care through distinct biologically driven therapies and outline the new challenges that these approaches expose.
