Review Articles

This Review synthesizes the current understanding of host–microbiota dynamics in patients with cancer and proposes to integrate microbiota management approaches guided by ecological principles in cancer care. Mathematical ecology could help to predict the risk of microbiota-related complications and guide treatment choices that minimize disturbance to microbial ecosystems, ultimately informing microbiota-targeted interventions that could improve responses to cancer treatments.

Immune-checkpoint inhibitors (ICIs) have improved lung cancer outcomes, although resistance to these agents presents a substantial challenge. This Review describes the progress made in developing the next generation of immunotherapies for non-small-cell and small cell lung cancers, including novel immune-checkpoint modulators, immune cell engagers, adoptive cell therapies and therapeutic vaccines, as well as the mechanisms by which these agents might overcome resistance to the current generation of ICIs.

Liquid biopsy-based tests have demonstrated potential as a minimally invasive and broadly applicable approach to simultaneously screen individuals for multiple cancer types. In this Review, Wan, Sasieni and Rosenfeld discuss the promises and limitations of such multi-cancer early detection tests as well as future directions for this field.

Patients with advanced-stage lung cancer might discontinue immune-checkpoint inhibitor (ICI) treatment for various reasons, including toxicities, disease progression or disease remission. Nonetheless, treatment options in this setting are often limited and some patients might derive benefit from re-administration of a previously received ICI. In this Review, the authors summarize the available data on ICI rechallenge, including the reasons for discontinuation and the feasibility of rechallenge in various clinical scenarios, and highlight important unaddressed research questions.

Despite being the second most lethal and the third most prevalent form of cancer, most cases of colorectal cancer (CRC) can be either detected at an early stage or prevented using screening colonoscopy with removal of precursor lesions. Nonetheless, universal colonoscopy is expensive and time consuming, and can be unpopular. Other less-invasive screening tests involving either faeces or more recently blood samples have the potential to improve overall CRC screening uptake and are an active area of research and development. In this Review, the authors describe the clinical utility of novel CRC screening methods such as multitarget stool DNA tests and blood cell-free DNA tests, including both the challenges and opportunities arising from their implementation.

Despite advances in drug development, some patients with non-small-cell lung cancer (NSCLC) have suboptimal responses to treatment. The authors of this Review provide an overview of the complexity of the tumour microenvironment in NSCLC, including the influence of patient-related factors, such as ageing, sex and health disparities, on the cancer–TME crosstalk, and discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC.

The composition of the gut microbiota has been implicated as a key determinant of not only the clinical efficacy but also the immune-related adverse effects (irAEs) of immune checkpoint inhibitors. This Review describes the reported correlations between alterations in the gut microbiota and irAEs, as well as their potential underlying mechanisms and possible predictive utility. Gut microbial interventions that might serve as new strategies for the management of irAEs are also discussed.

Anal squamous cell carcinoma (ASCC) is a rare malignancy, albeit with an increasing prevalence in most economically developed countries. Despite considerable advances in our understanding of the biology of ASCC, chemoradiotherapy (CRT) remains the standard-of-care therapy for most patients, albeit with promising data emerging on the role of CRT plus immune-checkpoint inhibitors in the metastatic setting. In this Review, the authors describe the biology of ASCC and relate this to the various attempts to improve outcomes via the development of more effective systemic therapies and/or combinations.

The development of companion diagnostic assays enabling the detection and quantification of HER2 expression and ERBB2 amplifications has provided an important early example that has informed the development of many companion diagnostics for the identification of other drug targets. However, the introduction of trastuzumab deruxtecan and, potentially, other novel antibody–drug conjugates has created the need for assays that are much more sensitive. In this Review, the authors describe the historical development of HER2 companion diagnostic assays in breast and other HER2-positive cancers and highlight the possible, future, more sensitive methods of HER2 detection and quantification that might provide the next generation of companion diagnostics.

Multiple myeloma is a malignancy at the forefront of measurable residual disease (MRD) assessment. In this Review, the authors describe the evolution of MRD analysis in multiple myeloma from technical and clinical standpoints, and discuss opportunities and challenges for MRD-guided management of this disease.

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.

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.

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.

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.

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.

Analysis of circulating tumour DNA (ctDNA) is commonly used for molecular profiling in patients with advanced-stage non-small-cell lung cancer (NSCLC). The authors of this Review summarize the available evidence on the potential utility of incorporating ctDNA in the management of those with early stage and locally advanced NSCLC and propose interventional studies to provide the necessary additional evidence.

Tumour-infiltrating lymphocytes (TILs) are crucial effectors of the anticancer immune response and are hypothesized to be key determinants the efficacy of immune-checkpoint inhibitors (ICIs). Herein, the authors review studies that have evaluated the roles of various TIL subsets as predictive biomarkers for ICIs, as well as opportunities, challenges and strategies for future research in this field.

Despite lower levels of most targetable alterations, a strong association with a history of smoking and generally higher levels of PD-L1 expression, patients with squamous non-small-cell lung cancer (LUSC) have inferior outcomes on immune-checkpoint inhibitors (ICIs) compared to those with non-squamous disease. In this Review, the authors describe the available evidence on the role of ICIs and of potential novel therapies in patients with LUSC, as well as highlighting important unresolved challenges and future research directions in this historically overlooked subtype.

In this Review, the authors discuss key clinical trials and therapeutic advances that have informed the current treatment landscape for cervical cancers of all stages, including refinement of surgical management approaches, the establishment of chemoradiotherapy, and the integration of anti-angiogenic agents, immune-checkpoint inhibitors and antibody–drug conjugates.