Review Articles

The oligometastatic state is generally considered to constitute an intermediate point along the spectrum of cancer dissemination at which the metastatic burden is limited and local ablative therapies can result in meaningful clinical benefit, and possibly even cure. In this Review, Katipally et al. reframe the oligometastatic phenotype as a dynamic state that expands beyond merely the number or size of metastases. They highlight important risk factors defining the metastatic spectrum that can inform both staging and therapy, and identify themes in the literature that might guide strategies to optimally combine metastasis-directed local therapies with modern systemic treatments.

After a frustratingly slow pace of development of new effective treatments for mesothelioma, single or dual therapy with immune-checkpoint inhibitors has substantially improved overall survival over previous standard-of-care therapies in various disease settings. The authors of this Review summarize the current evidence on immunotherapies for mesothelioma, focusing on strategies evaluated in randomized clinical trials and emerging predictors of response, and discuss future treatment opportunities.

Radiotheranostics enables the clinician to image and then target lesions using the same probe. Despite this appealing potential, interest in the field of radiotheranostics has long been constrained by a lack of expertise, high infrastructure costs and the availability of non-radioactive alternative approaches. Nonetheless, several recent successes have led to renewed research interest. In this Review, the authors summarize the current challenges and opportunities in this rapidly emerging area.

Neuroblastomas are tumours of sympathetic origins typically seen in infants (≤5 years of age). In this Review, the authors describe progress in the treatment of patients with neuroblastoma, which has resulted in considerable improvements in survival outcomes over the past several decades. The authors then summarize ongoing attempts to personalize therapy in patients with high-risk disease, and to safely de-escalate therapy in those with low-risk disease.

Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area.

Several PI3K pathway inhibitors are currently approved as cancer treatments; however, finding an acceptable therapeutic window to target this key signalling cascade linking cancer growth with metabolism has proven challenging and the clinical results to date have arguably been disappointing. In this Review, Vasan and Cantley discuss the effects of PI3K pathway alterations on signalling and metabolism in solid tumours as well as past and present efforts to improve the somewhat limited clinical efficacy of PI3K pathway inhibitors, with a particular focus on PI3Kα in breast cancers.

In the past decade, treatment devices that combine imaging with targeted irradiation have been developed to deliver MRI-guided radiotherapy (MRIgRT). This treatment modality uses motion management and biological targeting to improve local control rates whilst reducing the radiation delivered to non-malignant tissues. The authors of this Review describe the current state of MRIgRT, and the opportunities and challenges of this radiotherapy approach.

The tumour microenvironment includes various diverse immune cell types, each of which might influence tumour progression and response to treatment, particularly with immunotherapies. These cell types include different subtypes of B lymphocytes, which are often associated with tertiary lymphoid structures (TLS) and can have pro-tumour or anti-tumour effects, either through their classical function in antibody production and antigen presentation or other mechanisms. Herein, Fridman et al. discuss the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation, the potential of B cells and TLS as prognostic and/or predictive biomarkers, and novel approaches aiming to enhance the development of TLS and anti-tumour B cells for cancer therapy.

The interaction of tumour-associated macrophages (TAMs) with cancer and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. The authors of this Review examine the diversity of TAMs in various cancer indications, which is being revisited with the advent of single-cell technologies, and discuss the functional roles of different TAM states, the prognostic and predictive value of TAM-related signatures as well as approaches involving TAMs that are currently being or will soon be tested in clinical trials.

Photoacoustic imaging is a novel imaging technique that provides scalably high levels of spatial resolution at rapid acquisition speed, without the need for radiation or exogenous contrast agents. In this Review, the authors describe the emerging role of this technology in the screening, diagnosis and management of patients with cancer, and provide an overview of the future implementation of this technology.

Chimeric antigen receptor T cells have revolutionized the treatment of patients with certain haematological malignancies. Nonetheless, an optimal approach to lymphodepleting chemotherapy and/or bridging therapies has yet to be defined in patients receiving these agents. In this Review, the authors describe the various lymphodepletion and/or bridging therapy strategies used, and highlight the need for prospective comparisons in order to determine the safest and most effective approach.

Vaccination against COVID-19 confers robust protection from severe disease. However, the extent to which this applies to patients with cancer remains uncertain given that these patients were excluded from most of the pivotal studies. In this Review, the authors provide an overview of the efficacy and immunogenicity of COVID-19 vaccines in patients with cancer, and discuss alternatives to vaccination for those who might be unable to develop a proficient immune response following vaccination.

Gastrointestinal stromal tumour (GIST) is the most common form of sarcoma and has become a paradigm of precision medicine owing to the fact that almost all patients harbour one of several known molecule drivers, most of which can be targeted therapeutically. Nevertheless, novel therapeutic strategies are required to overcome the intrinsic resistance of certain subtypes of GIST to existing treatments as well as the acquired resistance that eventually arises in initially sensitive subtypes. This Review describes the biology of GIST, the evolution of the current treatments for this cancer, and the emerging therapeutic agents and approaches that might overcome the remaining clinical challenges.

Antibodies targeting PD-1 or its ligand PD-L1 have revolutionized cancer therapy. Increased understanding of the mechanisms regulating PD-L1 has revealed links with several important oncogenic signalling pathways. Herein, the authors review the transcriptional, post-transcriptional and translational regulation of PD-L1 expression in cancers as well as the diverse post-translational modifications, including phosphorylation, palmitoylation, glycosylation, acetylation and ubiquitination, that affect PD-L1 stability and activity. They also discuss the possibility to simultaneously target key oncogenic pathways and modulate PD-L1 expression using small-molecule agents, which have potential advantages over or might synergize with anti-PD-1/PD-L1 antibodies.

The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing rapidly in most developed countries. In this Review, the authors provide an overview of the epidemiology, molecular biology and treatment of HPV-positive OPSCC, including discussions of the role of treatment de-escalation and emerging novel therapies.

Immune-checkpoint inhibitors (ICIs) have dramatically improved the outcomes of patients with advanced-stage solid tumours, including the potential for long-term remission in a subset. However, long-term follow-up data reveal a risk of chronic toxicities from these agents, which can have important quality-of-life implications. In this Review, the authors describe the current level of evidence of chronic toxicities of ICIs and their implications for patients

Multiple myeloma and its precursor stages, monoclonal gammopathy of undetermined significance and smouldering multiple myeloma, have a considerable degree of genetic heterogeneity. The authors of this Review discuss how single-cell studies in these individuals are enabling the mutational and phenotypic characterization of cells within the bone marrow tumour, immune microenvironment and peripheral blood to eventually guide early diagnosis, risk stratification and treatment strategies.

A variety of cytokines have diverse antitumour and/or pro-tumour activities and, accordingly, alterations in cytokine networks contribute to cancer development and progression. Therefore, cytokines and their receptors have long been investigated as therapeutic agents or targets in oncology, although with mostly disappointing results. Herein, Propper and Balkwill discuss the lessons learnt from initial clinical trials of monotherapy approaches as well as subsequent strategies to better leverage cytokines and cytokine antagonists in the treatment of solid tumours.

Circular RNAs (circRNAs) are a novel class of primarily non-coding RNAs with increasingly recognized roles in cancer development and progression through diverse mechanisms of action. Herein, the authors review the current understanding of circRNA biogenesis, regulation, physiological functions and pathophysiological roles in cancer. They also discuss the clinical potential of circRNAs as biomarkers, therapeutic agents and drug targets in oncology as well as research controversies, technical issues and biological knowledge gaps that need to be addressed before this promise can be realized.

Patients receiving cytotoxic therapies for cancer have an increased risk of cognitive and functional decline that is usually associated with ageing. In this Review, the authors describe how cancer therapies can enhance physiological ageing processes and highlight the potential for interventions that could potentially ameliorate these long-term adverse events in patients receiving active treatment for cancer and in cancer survivors.