Browse Articles

Tumours with deficient DNA mismatch repair (dMMR) leading to a microsatellite instability-high (MSI-H) phenotype are characterized by a high burden of immunogenic mutations and, thus, an immunological ‘hot’ microenvironment that is associated with high sensitivity to immune-checkpoint inhibitors. In this Review, the authors discuss the epidemiology, biology, pathogenesis, clinical diagnosis and treatment of MSI-H/dMMR tumours, highlighting idiosyncrasies associated with specific pathogenetic alterations and tumour histologies.

Surrogate end points in drug regulation are thought to reduce the time required to bring new drugs to market; however, only a few of the drugs approved on the basis of these outcomes have subsequently demonstrated robust improvements in overall survival (OS). If the FDA and other regulators were to shift their priority to patient-centred outcomes, such as OS, I argue that such a shift would probably lead to fewer, but also a higher standard of drugs entering the market, potentially with faster approval decisions because novel therapies would initially be tested in later lines and in patients with a worse prognosis.

Stereotactic radiosurgery (SRS) has been established as a key therapeutic modality for the management of brain metastases. In this Review, an international group of experts discuss the expanding opportunities for SRS, including application for larger brain metastases and cumulative intracranial tumour volumes, fractionated delivery, neoadjuvant use and combinatorial approaches with modern systemic therapy, as well as associated challenges and remaining questions.

HER3 is emerging as a promising therapeutic target that is often overexpressed or genetically altered across diverse solid tumour types. This Review describes the landscape of HER3 alterations in cancer and their prognostic implications, the roles of HER3 in oncogenesis and resistance to targeted therapies, and the ongoing clinical development of agents targeting HER3.

Acquired resistance is a common occurrence among patients with oncogene-driven non-small-cell lung cancer receiving targeted therapies. Monitoring of circulating tumour DNA in liquid biopsy samples provides an appealing, minimally invasive method of monitoring for acquired resistance in this setting. However, research into detecting mechanisms of acquired resistance in liquid biopsy samples has thus far been limited by various challenges. In this Perspective, the authors describe the available data on detecting mechanisms of acquired resistance to targeted therapies in patients with non-small-cell lung cancer, as well as the various challenges to progress, such as a lack of a consensus definition of acquired resistance, and other inconsistencies in the approach to detecting and investigating these alterations.

First-line treatment of advanced-stage classic Hodgkin lymphoma (HL) has successfully entered the era of targeted agents based on results from the phase III German Hodgkin Study Group HD21 and US intergroup S1826 trials. Although these trials bring about important advances, many uncertainties remain and the outcomes of all patients with HL can be further improved.

Advanced-stage hepatocellular carcinoma is currently treated with various anti-PD-(L)1 antibody-containing regimens. Now, a triplet combining the anti-TIGIT antibody tiragolumab with one of these regimens has demonstrated promising efficacy in a phase Ib/II trial, although these data will need to be confirmed. This study highlights the value of umbrella trials while also raising questions regarding the most effective immune-targeting strategies in patients with this disease.

Immunotherapies, predominantly immune-checkpoint inhibitors and chimaeric antigen receptor T cells, have transformed oncology. Nonetheless, these systemically administered agents have several limitations, including the risk of off-target toxicities and a lack of activity owing to an inability to overcome an immunosuppressive tumour microenvironment (TME). In this Review, the authors describe the potential to overcome these challenges using functionalized nanomaterials that are designed to release a wide range of immunotherapeutic cargoes in response to specific TME characteristics, including hypoxia, differences in pH, the presence of specific enzymes, reactive oxygen species and/or high levels of extracellular ATP.

Patients with advanced-stage cancer seek treatments that prolong survival and improve quality of life. We analysed new anticancer drug indications approved by the FDA and EMA between 2020 and 2023 using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale quality-of-life checklist. Our findings highlight critical gaps in the availability and reliability of quality-of-life outcomes from the pivotal trials that support these approvals.

Single-cell RNA sequencing has transformed our understanding of the biology of cancer cells and that of nonmalignant cells present in the tumour microenvironment. However, how this new knowledge can be translated into improved outcomes for patients often remains uncertain. In this Review, the authors describe the results of single-cell RNA analyses of samples from patients with cancer with an emphasis on how the findings of these studies have, or are anticipated to lead to, improved patient outcomes, with a focus on four key aspects: refinement of tumour subtyping, characterization of treatment-induced changes, identification of gene expression programmes predictive of treatment response and resistance, and the discovery of novel therapeutic targets.

In a recently reported study, a novel engineered oncolytic Newcastle disease virus encoding porcine α1,3-galactosyltransferase was evaluated in monkeys with CRISPR-induced primary hepatocellular carcinoma and in a phase I clinical trial. The virus induced hyperacute tumour rejection and an objective response rate of 35% in 20 evaluable patients. This approach highlights the promises and challenges of oncolytic virus drug development.

The thought-provoking SONIA trial showed that patients with hormone receptor-positive, HER2-negative advanced-stage breast cancer receiving deferred (second-line) versus first-line cyclin dependent-kinase (CDK) 4/6 inhibitors have noninferior progression-free survival after second-line treatment; such an approach also results in substantial cost savings. Herein, we discuss some important limitations of this trial and argue that, owing to their effect on overall survival, CDK4/6 inhibitors should remain the standard-of-care first-line therapy.

CD19-targeted CAR T cells have transformed the management of patients with relapsed and/or refractory large B cell lymphoma, and these therapies are increasingly being administered as earlier-line therapies. Nonetheless, the prognosis of these patients is often difficult to predict, with various prospective and real-world studies suggesting that a wide range of factors are associated with treatment outcomes. In this Review, the authors summarize these various associations as well as their implications for patient selection and management.

The authors of this Perspective evaluate the developments in the use of artificial intelligence (AI) in digital pathology for oncology applications between 2019 and 2024, addressing technological innovations, regulatory trends, implementation and financial implications. Importantly, they explore the current landscape of clinical deployment, highlighting future opportunities for the integration of AI into clinical oncology routine practice.

Recent data from the FELIX trial evaluating obecabtagene autoleucel in patients with relapsed and/or refractory B acute lymphoblastic leukaemia (R/R B-ALL) suggest that this novel intermediate-affinity CD19-directed chimeric antigen receptor (CAR) T cell therapy is associated with a reduced incidence of severe immune-mediated toxicities compared with other commercially available CAR T cell products. The increasing number of therapies available for B-ALL makes treatment selection and sequencing of therapies increasingly challenging.

DeepGEM, an artificial intelligence (AI)-based model, accurately predicts the presence of key genomic alterations in histological slides prepared from samples obtained from patients with lung cancer. This approach provides a cost-effective alternative to genomic testing, generates spatial mutation maps and might support personalized treatment strategies. Validated in diverse datasets, DeepGEM highlights the potential of AI to transform precision oncology and improve global healthcare equity.