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.

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.

This comprehensive Review describes the biological function of the mismatch repair (MMR) machinery, the genomic sequelae of defects in this machinery and the roles of hereditary or sporadic MMR deficiency in cancer predisposition and/or tumour development. The authors also discuss the clinical implications of MMR deficiency with a specific focus on diagnostic approaches, therapeutic strategies and mechanisms of resistance to immune-checkpoint inhibitors.

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.

Some of the most consequential conflicts in oncology and medicine overall are not financial; these remain poorly defined and weakly regulated. Here we offer a policy-relevant definition and examine how reputation, ambition, ideology and institutional loyalty can shape research, guidelines, policy and hiring decisions. We argue for structural safeguards to preserve trust in medicine.

Drug-induced interstitial lung disease (DIILD) is emerging as a hidden toll of modern oncology. Diagnosis of DIILD is confounded by non-specific symptoms and the absence of validated biomarkers, leaving clinicians to navigate heterogeneous, drug-specific guidelines. Herein, we discuss this predicament and advocate a shift from reactive management towards proactive survivorship.