Review Articles

By combining multiple MRI sequences, each providing different but complementary information about the tumour microenvironment (TME), multiparametric MRI (mpMRI) enables non-invasive assessment of the heterogeneous features of the TME components. The authors of this Review describe the role of mpMRI in the non-invasive characterization of the TME, presenting examples of its utility in cancer detection, staging and assessment of response to therapy, and considering future applications for personalized integrated diagnostics.

Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.

Ovarian cancer, accounting for 4.7% of cancer deaths in women in 2020, remains highly prevalent globally. Nonetheless, owing to changes in environmental exposures, the approach to preventive measures and disease classification, both incidence and mortality have been declining in economically developed countries since the early 2000s. Conversely, parts of Asia and eastern Europe have seen increases in the incidence of ovarian cancer over this period of time. In this Review, the authors summarize the epidemiology of ovarian cancer, including the roles of the various risk factors and the potential for prevention.

The development and successful phase III testing of the anti-claudin 18.2 antibody zolbetuximab has provided a novel targeted therapy for the 30–40% of patients with strongly claudin 18.2-positive gastric cancers. Furthermore, the development of an effective targeted therapy for a target that does not have a driver role in cancer development provides a novel drug development paradigm. In this Review, the authors describe the development of claudin 18.2-targeted therapies, including zolbetuximab, as well as novel therapies, including chimeric antigen receptor (CAR) T cells, antibody–drug conjugates and bispecific antibodies, all of which have the potential to expand the number of patients who can derive benefit from claudin 18.2-targeted therapies in the near future.

Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.

FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.

Patients with early stage hepatocellular carcinoma typically undergo resection, liver transplantation or local ablation; however, 30–50% will have disease recurrence at 3 years. The authors of this Review describe the tumour immune microenvironment and mechanism of action of immunotherapies, and discuss the available evidence from phase II/III trials of neoadjuvant and adjuvant treatment approaches in this setting.

Increasing evidence indicates that signalling networks activated downstream of oncogenic alterations contribute fundamentally to cancer immune evasion, including by promoting the accumulation of regulatory T (T_reg) cells and other immunosuppressive cells in the tumour microenvironment (TME). Herein, the authors discuss the mechanisms via which cancers engage T_reg cells to evade antitumour immunity, as well as the characteristics of T_reg cells in the TME and their roles in resistance to immune-checkpoint inhibitors. Considering these aspects, they propose the concept of ‘immuno-genomic cancer evolution’ for tumorigenesis and the related paradigm of ‘immuno-genomic precision medicine’, postulating that the specific characteristics of cancer, especially genetic profiles that correlate with particular immunosuppressive networks in the TME, are likely to inform individualized strategies for combining molecularly targeted agents with immunotherapies.

Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR) is a mediator of the cellular replication stress response that, upon activation, initiates a cascade of coordinated reactions that ultimately enables DNA repair. This biological function makes ATR an attractive therapeutic target in cancers with elevated replication stress or DNA-repair deficiency. This Review discusses the currently available results from clinical trials testing ATR inhibitors as well as challenges and solutions in the development of this therapeutic class.

Dendritic cells (DCs) are antigen-presenting cells that function at the interface between innate and adaptive immunity, thereby acting as key mediators of antitumour immune responses and immunotherapy efficacy. In this Review, the authors outline the emerging complexity of intratumoural DC states that is being revealed through single-cell analyses as well as the contributions of different DC subsets to anticancer immunity and the activity of immune-checkpoint inhibitors. The authors also discuss advances in the development of DC-based cancer therapies and considerations for their potential combination with other anticancer therapies.

Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAF^V600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.

Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.

Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that accumulate in the tumour microenvironment, where they exert various immunosuppressive mechanisms as well as a variety of other tumour-promoting effects. Herein, the authors provide an overview of MDSC generation and their accumulation in tumours, describe the interplay between MDSCs and various other cell types found in tumours, and review the mechanisms by which MDSCs promote tumour development and progression, metastasis, and resistance to treatment. They also discuss the effects of established treatment modalities on MDSCs as well as implications for the development of novel therapeutic strategies targeting these cells.

The discovery of ERBB2 as a gene frequently amplified and/or overexpressed in breast cancers and of its product HER2 as a biomarker has spurred the development of various targeted therapies. As a result, the prognosis of patients with advanced-stage HER2-positive breast cancer has greatly improved in the past decades. The authors of this Review describe the development of the current treatment landscape for these patients and discuss how to address resistance to further improve outcomes.

p53, encoded by TP53, the commonest mutated gene in cancer, is an appealing target for systemic anticancer therapies including those designed to restore p53 function. Thus far, and despite promising preclinical data and several clinical trials, no p53-restoring systemic therapy has been approved for therapeutic use. Despite this limited success, several research efforts are ongoing. In this Review, the authors summarize the role of p53 in cancer with a focus on the complexity of p53 function and how this relates to clinical attempts to restore at least some of these functions.

Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy have become the standard-of-care therapy for patients with advanced-stage hormone receptor-positive breast cancer. However, this success has created several challenges, such as the need to better understand resistance to these agents and develop novel therapies accordingly. Here, the authors provide an update on the clinical activity of the established CDK4/6 inhibitors along with a summary of ongoing research efforts attempting to address the new challenges created by the success of these agents.

Patients with advanced-stage urothelial cancer (aUC) continue to have poor long-term survival outcomes. However, developments in the past 5 years, most notably the availability of maintenance therapy with the anti-PD-1 antibody avelumab, are beginning to change this issue. In this Review, the authors provide an overview of the treatment of patients with aUC, including considerations of the various promising new therapeutic modalities and how they might improve clinical outcomes.

Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.