Reviews & Analysis

Patients with unresectable stage III non-small-cell lung cancer without EGFR or ALK mutations typically receive the PACIFIC regimen — concurrent chemoradiotherapy (cCRT) followed by consolidation with durvalumab â€” whereas those with EGFR-mutant disease typically receive cCRT followed by an EGFR inhibitor. Nonetheless, a subset of patients within this heterogeneous group might be able to completely avoid consolidation therapy, whereas others are unable to tolerate cCRT. In this Review, the authors describe the standard-of-care approach in this setting, followed by discussions of treatment optimization for specific subgroups, as well as important future research questions.

Extracellular vesicles (EVs), a diverse range of membrane-delimited particles, have multiple cellular functions and, when released by cancer cells, can promote tumour growth and metastatic dissemination. The authors of this Review describe advances in the development of EVs as biomarkers and cancer therapeutics, focusing on clinical translation of EVs into diagnostic and therapeutic clinical tools.

Epstein–Barr virus (EBV) infection has a key aetiological role in endemic nasopharyngeal carcinoma (NPC). The authors of this Review discuss advances in NPC screening, which leverage the detection of either plasma EBV DNA or serum antibodies targeting EBV antigens, as well as in prevention, which relies on prophylactic and therapeutic vaccines for NPC.

Patients with advanced-stage pancreatic ductal adenocarcinoma often have dismal outcomes, despite an initial response sometimes to standard-of-care chemotherapy. This treatment refractoriness partly reflects the effects of the tumour microenvironment (TME), which is highly heterogeneous but can include a dense desmoplastic stroma as well as various immune cell and cancer-associated fibroblast populations, most of which collectively promote resistance to treatment and disease progression. In this Review, the authors summarize the role of the TME in determining the outcomes of patients with pancreatic ductal adenocarcinoma, and consider novel therapeutic approaches that might promote the development of a tumour-suppressive TME.

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing the treatment of haematological malignancies, but expanding applicability to solid tumours presents substantial challenges. This Review describes key strategies to optimize CAR T cell therapy for solid tumours across areas spanning from target selection to response and safety evaluation.

Final results from the phase I AMPLIFY-201 trial show that ELI-002 2P, a therapeutic cancer vaccine targeting mutant KRAS, elicits polyfunctional T cell responses in patients with minimal residual disease-positive pancreatic or colorectal cancer. Importantly, the magnitude of this response correlated with improved clinical outcomes. Herein, we discuss how these results could set the stage for ongoing randomized trials.

Several persistent challenges limit the efficacy and applicability of adoptive T cell therapies for cancer, including suboptimal function and/or persistence in vivo, a narrow range of targetable antigens and complex manufacturing processes. This Review discusses the potential of ‘CRISPR 2.0’ precision gene-editing platforms, such as base editing and prime editing to address all of these challenges, and describes the progress made towards clinical translation of these technologies.

Targeted radionuclide therapy (TRT) is a therapeutic modality that combines the strengths of radiotherapy and systemic molecularly targeted therapy. Over the past few years, new TRT agents have been developed against an expanding array of molecular targets, particularly in cancers with limited treatment options. The authors of this Review discuss these advances, focusing on what constitutes an optimal target and discussing lessons learned from past experience in order to broaden the scope of TRT.

The Radiomics Quality Score (RQS) was developed to assess the rigour of studies using radiomics, a tool for medical imaging analysis. The RQS has been widely used in the field and now needs an update (RQS 2.0) to address contemporary needs. The authors of this Review introduce RQS 2.0, which integrates radiomics readiness levels to provide a structured framework towards clinical implementation.

Patients with acute myeloid leukaemia are often unable to tolerate intensive chemotherapy, and the outcomes of these patients have improved considerably following the availability of regimens containing the BH3 mimetic venetoclax. Nonetheless, not all of these patients will respond to venetoclax, and virtually all will ultimately develop resistance, indicating a need for novel treatment strategies targeting this pathway. In this Review, the authors describe the development of BCL-2 inhibitors, discuss mechanisms of resistance and summarize ongoing research efforts aimed at optimizing the therapeutic benefit of these agents.

The landmark CHALLENGE trial has revealed that a 3-year structured, behaviourally supported exercise intervention substantially improves both disease-free and overall survival in patients with resected phase II–III colon cancer, marking a genuine paradigm shift in survivorship care. By demonstrating modification of the course of disease rather than merely symptom alleviation, these results elevate exercise from ancillary support to evidence-based therapy and should compel oncology teams to embed expert-guided exercise into routine care.

Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage driver-negative non-small-cell lung cancer (NSCLC), although most patients will ultimately have disease progression on these agents and the most effective treatment approach in this scenario remains uncertain. In this Review, the authors describe the outcomes in patients receiving second-line therapy for advanced-stage NSCLC and provide an overview of emerging therapies and future areas of research in this challenging clinical setting.

The SERENA-6 trial assessed a paradigm-shifting approach to personalized cancer therapy in patients with advanced-stage breast cancer, in which therapy was switched upon the identification of resistance-related mutations in ESR1 in circulating tumour DNA (ctDNA). Herein, we discuss how the results of this trial challenge the standard-of-care management for these patients, in whom therapy changes are otherwise undertaken only after radiographic and/or clinical progression.

Recent clinical data indicate that infection with the common β-herpesvirus cytomegalovirus (CMV) confers beneficial effects on the T cell compartment that are associated with superior outcomes following immunotherapy in patients with melanoma. These findings warrant further studies of novel therapeutic strategies and biomarkers that might better predict clinical response to and toxicities of immunotherapy, based on systemic immune status.

Cancer of unknown primary (CUP) constitutes a diagnostic quandary and has a dismal prognosis, with standard empirical chemotherapy providing limited benefit. This Review outlines diagnostic innovations that are improving tissue-of-origin prediction as well as novel treatment strategies that have shown promise for improving outcomes in patients with CUP.

Despite advances in cancer therapy, the persistent challenge of treatment resistance and particularly multidrug resistance remains a substantial barrier to further improvements in patient outcomes. In this Review, the authors discuss preclinical and clinical advances in understanding multidrug resistance, with an emphasis on resistance to chemotherapies and targeted therapies, as well as the progress made in translating these findings into novel strategies to overcome this challenge and thus improve patient outcomes.

Next-generation, oral selective oestrogen receptor degraders (SERDs) have been shown to improve outcomes in patients with advanced-stage oestrogen receptor (ER)-positive, HER2-negative breast cancer, particularly those with acquired ESR1 mutations. Now, the proteolysis-targeting chimera (PROTAC) SERD vepdegestrant, which induces ER degradation directly rather than indirectly, has also demonstrated efficacy in this setting, raising questions over the optimal choice and sequencing of treatments.

Despite several decades of research that has revealed roles in the development and progression of many solid tumours, clinical translation of research targeting epithelial–mesenchymal transition (EMT) has thus far been limited. In this Review, the authors provide a summary of the role of EMT in cancer development and progression in the context of this lack of clinical translation, summarize the current status of direct or indirect EMT-modulating agents in clinical development, and highlight the major barriers to the development of EMT-related clinical interventions.

MET mutations, amplifications and fusions and MET overexpression are promising therapeutic targets across various cancers. In this Review, the authors summarize the prevalence, molecular diagnosis and prognostic implications of these alterations and discuss the clinical efficacy and toxicity profiles of diverse MET-targeted therapies, including tyrosine-kinase inhibitors, monoclonal or bispecific antibodies and antibody–drug conjugates.

Radiotherapy has an established role in the treatment of many patients with cancer, with evidence suggesting that this modality can also have immunostimulatory effects in certain scenarios. More recently, evidence has emerged supporting a role of the microbiome in influencing the incidence and severity of toxicities in patients receiving radiotherapy as well as in mediating possible synergy with other therapeutic interventions, including immunotherapy. In this Review, the authors explore the clinical potential of these emerging relationships.