Review Articles in 2022

Although radiotherapy affects multiple cellular pathways, treatments are generally planned with the assumption that all tumours respond similarly to radiation. The authors of this Review summarize the effect of various pathways activated by radiotherapy on tumour responses to radiotherapy and present the current knowledge on genomic classifiers designed to inform treatment decisions.

Despite a considerable increase in research output over the past decades, the translation of radiomic research into clinically useful tests has been limited. In this Review, the authors provide 16 key criteria to guide the clinical translation of radiomics with the hope of accelerating the use of this technology to improve patient outcomes.

Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.

Neuroendocrine neoplasms (NENs), which can develop in almost any organ and range from indolent neuroendocrine tumours (NETs) to rapidly progressive and fatal neuroendocrine carcinomas (NECs), have historically been approached in a siloed manner according to their specific tissue of origin. However, NETs and NECs across different sites of origin often share genomic and phenotypic characteristics. In this Review, the authors discuss both the clinical and biological commonalities as well as key organ-specific differences of NENs, with a focus on those of the gastrointestinal system and lung. Moreover, they advocate for a cross-cutting, tissue-agnostic approach to drug development for these rare tumours that might enable advances in one disease entity to accelerate research in others, ultimately improving patient care.

Owing to several limitations, including elimination by the immune system and a lack of tumour specificity, systemically administered synthetic nanoparticles are used for a limited range of cancer indications. In this Review, the authors describe the potential of cellular nanoparticles (comprising a cell membrane coating around a synthetic core) to overcome these issues as well as their application in drug delivery, phototherapy and immunotherapy.

Systemic therapies for early-stage disease have been tested in clinical trials for decades. The authors of this Review provide an overview of the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era, focusing on design, end points and biomarkers that, together, could enable the delivery of more personalized treatment.

Either alone or in combination, chemotherapy remains the mainstay treatment for most human malignancies. This treatment modality is associated with a high burden of chemotherapy-associated adverse events (CAAEs) that greatly affect patients because of their considerable morbidity, mortality and costs. Kuderer et al. discuss the pathophysiology, management and risk factors of the most common acute CAAEs with a major effect on survival, quality of life, function and/or continuation of optimal therapy.

T cells are key effectors of immunotherapies that have revolutionized the treatment of cancer; however, chronic exposure to tumour-associated antigens can result in progressive loss of T cell effector functions and self-renewal capacity, a state termed ‘T cell exhaustion’ that is believed to limit the efficacy of immunotherapy. This Review synthesizes the new immunobiological insights that present a more nuanced view beyond T cell exhaustion being entirely undesirable and indicate that this hypofunctional state might be as much a reflection as it is the cause of poor tumour control. Hence, the authors describe how, in certain contexts, interruption of this programme could impair T cell persistence and discuss interventions to mitigate the development of T cell exhaustion that might ultimately improve clinical outcomes.

A high serum lactate dehydrogenase (LDH) level is generally associated with an inferior outcome in patients with most tumour types. LDH is also known to have immunosuppressive and/or tumour-promoting effects, suggesting a potentially broader role for this enzyme in clinical oncology. In this Review, the authors provide a holistic overview of the current role of LDH in both cancer biology and oncology, and highlight possible areas of future research interest, including the development of novel therapies targeting LDH.

Clinical research needs support from preclinical models that consider the biology and genetics of human cancers during treatment, such as patient-derived xenograft (PDX) models. The authors of this Review discuss how PDX models have been used in the past decade for precision oncology and present emerging approaches that could broaden the application of these models.

Peritoneal surface malignancies (PSMs) typically have a poor prognosis, although considerable advances in the understanding and management of these malignancies have been made over the past decade. This Review comprehensively describes the improvements in knowledge of the biology, assessment and classification, perioperative and surgical management, systemic treatment and pre-emptive management of PSMs. The authors also outline future directions for research in this field.

The incidence of early-onset forms of many cancers (defined as cancers diagnosed in individuals <50 years of age) has increased in a number of countries over the past several decades. The underlying reasons for this apparent increase probably include greater use of screening programmes, but also changing patterns in early-life exposures. In this Review, the authors describe the emerging global increase in the incidence of early-onset cancers and suggest changes that might address this situation.

The entry of cells into senescence can act as a barrier to tumorigenesis; however, in certain contexts senescent malignant and non-malignant cells can acquire pro-tumorigenic properties. The authors of this Review discuss the cell-intrinsic and cell-extrinsic mechanisms involved in both the antitumorigenic and tumour-promoting roles of senescent cells, and describe the potential of various senolytic and senomorphic therapeutic approaches in oncology.

The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.

Advances in circulating tumour DNA (ctDNA) detection and analysis are beginning to be implemented in clinical practice. Nonetheless, much of this development has thus far focused on plasma ctDNA. Theoretically, all bodily fluids, including urine, cerebrospinal fluid, saliva, pleural fluid and others, can also contain measurable ctDNA and can provide several advantages over the reliance on plasma ctDNA. In this Review, Tivey et al. describe the potential roles of ctDNA obtained from non-plasma sources in optimizing the outcomes of patients with cancer.

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.