After decades of investment, antibody-drug conjugates (ADCs) are finally demonstrating their potential, marked by a growing number of clinical approvals, applications in earlier lines of treatment and integration into drug combinations, including immunotherapies. This progress has spurred investment in developing new ADCs and expanding the use of approved ADCs in clinical practice. The design of ADCs is complex, involving multiple molecular components that interact with both tumour and host tissue microenvironments. In this Review, we explore the molecular and immunological factors influencing ADC efficacy and toxicity. We describe how the molecular components of ADCs determine their systemic, tissue and cellular distribution, which ultimately dictates therapeutic efficacy. These interactions also determine the toxicity profile and set limitations on maximum dosing. Finally, we discuss the impact of ADC treatment on immune cells, emphasizing the distinct but interconnected roles of immunogenic cell death, activation of immune cells such as dendritic cells and antibody-Fc interactions. These mechanisms are crucial for increasing efficacy beyond the direct cytotoxic effects of the payload. By providing insights into the intricate interactions of ADCs, this Review aims to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs.

Resisting cell death is a pivotal hallmark of cancer and one of several increasingly actionable functional capabilities acquired by cancer cells to sustain their malignant state. Since the early 2000s, the discovery of multiple regulated cell death programmes has intensified interest in targeting these maladaptive traits that cancer cells employ to resist cellular demise. Among these, ferroptosis - the lethal outcome of iron-dependent (phospho)lipid peroxidation - stands apart from other regulated cell death mechanisms, as it is persistently suppressed while lacking an activating signal. In cancer research, ferroptosis has garnered considerable attention, with growing evidence suggesting that its deregulation intersects with other hallmarks of malignancy, thus positioning it as a pleiotropic target. However, in the absence of approved ferroptosis-based drugs and despite substantial advances in understanding the metabolic manoeuvres of cancer cells to evade ferroptosis, its heralded translational value remains somewhat speculative at this stage. This Review reconciles the biochemical foundation of ferroptosis, the evidence supporting its role in cancer biology and the potential strategies for rationalizing targeted therapies to induce ferroptosis-prone states in malignancies. Building on this foundation, we explore contentious issues surrounding ferroptosis, including its implications for immunogenicity and redox imbalances in cancer. Finally, we address critical considerations such as therapeutic windows and biomarkers of ferroptosis, which are prerequisites for successful translation into clinical oncology.

Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and applying deconvolution methods, considering the unique complexities of tumour tissues, data availability and method assumptions. We detail 43 deconvolution methods and outline how different approaches serve distinctive applications in cancer research: from understanding tumour-immune surveillance to identifying cancer subtypes, discovering prognostic biomarkers and characterizing spatial tumour architecture. By examining the capabilities and limitations of these methods, we highlight emerging trends and future directions, particularly in addressing tumour cell plasticity and dynamic cell states.

During anticancer therapy, patients with cancer are often prescribed medications to combat concomitant health conditions and ameliorate cancer-associated side effects. Despite emerging evidence that many commonly prescribed medications have immunomodulating properties, surprisingly little is known about their interactions with immune checkpoint inhibitors (ICIs) in the treatment of cancer. This Review provides an overview of recent advances characterizing the reported impact of concomitant drug use on ICI-mediated therapeutic response and associated immune-related adverse events, and the potential to repurpose immunomodulatory drugs for other comorbidities to enhance ICI treatment efficacy.

Within the tumour immune microenvironment (TIME), neutrophils can undergo NETosis to release neutrophil extracellular traps (NETs), which are protein-decorated DNA webs that promote cancer progression, metastasis and immune evasion. NETs promote cancer progression by fostering an immunosuppressive, pre-metastatic niche in regional lymph nodes prior to overt metastasis. Anticancer therapies such as immune checkpoint inhibitors, chemotherapy and radiation therapy can induce the formation of NETs, which can facilitate subsequent cancer invasion, migration, metastasis and recurrence through several mechanisms that dampen antitumour immune responses and sequester neoplastic cells. Precision blood and tumour testing for the NET burden could inform both patient prognosis as well as eligibility for treatments aimed at targeting NETosis, NETs and/or neutrophils. The importance of staging with other patient and treatment factors will thus inform the design of clinical trials evaluating NET-directed therapies. In this Review, we highlight our recent understandings of NET biology in cancer, and emphasize the translational data available, as well as the need for further clinical trials evaluating NETs and NET-directed therapies.

Macropinocytosis is a nutrient-scavenging process that enables cells to engulf large volumes of extracellular fluid and solutes through dynamic plasma membrane ruffling. In cancer, this evolutionarily conserved process is frequently hijacked to meet the heightened metabolic demands of malignant cells, particularly under conditions of nutrient deprivation. Through macropinocytosis, tumour cells internalize diverse extracellular components - including proteins, nucleotides, lipids, ions and debris from dead cells - which are subsequently degraded in lysosomes and recycled to support biosynthesis and energy production. This process is tightly regulated by oncogenic signalling pathways and cues from the tumour microenvironment, including those associated with oncogene activation, loss of tumour suppressors and hypoxia. Beyond facilitating tumour growth and metabolic adaptation, macropinocytosis is implicated in resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy. When excessively activated, it can also lead to methuosis, a form of non-apoptotic cell death characterized by macropinosome overload. This Review outlines the molecular mechanisms and functional consequences of macropinocytosis in cancer, highlighting its dual potential as a metabolic vulnerability and a route for therapeutic delivery. Continued investigation into its regulation, context-specific roles and pharmacological modulation may uncover new opportunities for combination therapies and precision cancer treatment.

Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion - which is characterized by repression of the effector functions and proliferative potential of T cells - has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy.

FLASH radiotherapy has the potential to improve both patient quality of life and outcomes by delivering radiation at ultrahigh dose rates to effectively target tumours while sparing healthy tissues. However, the differential sensitivity of healthy tissues versus tumours to FLASH radiotherapy remains unexplained. In this Perspective, we hypothesize that FLASH radiotherapy distinguishes healthy tissues from tumours based on subtle functional and structural biological differences. We identify commonalities present in the various healthy tissues that are spared by FLASH radiotherapy that might be lost during tumorigenesis. We also propose that a specific class of proteins, termed long-lived proteins, define a critical radiolytic target that are present in nearly every healthy tissue that is FLASH radiotherapy resistant yet are absent in tumours. We extend this structural hypothesis further by suggesting that tumour and extracellular matrix rigidity affects sensitivity to changes in radiotherapy dose rate, where more rigid and dense desmoplastic tumours are more sensitive to FLASH radiotherapy than those possessing more elasticity. Substantiating these concepts experimentally may provide a new and generalized mechanism of action of radiation effects and may therefore inform clinical trial designs by identifying those tumour subclasses expected to exhibit optimal responses to FLASH radiotherapy.

Resistance to cell death is a hallmark of cancer, driving tumour progression and limiting therapeutic efficacy. Metabolic cell death pathways have been identified as unique vulnerabilities in cancer, with ferroptosis being the most extensively studied, alongside the more recently discovered pathways of cuproptosis and disulfidptosis - each triggered by distinct metabolic perturbations. In this Review, we examine the molecular mechanisms and regulatory networks that govern these forms of metabolic cell death in cancer cells. We further examine the potential crosstalk between these pathways and discuss how insights gained and challenges encountered from extensive studies on ferroptosis can guide future research and therapeutic strategies targeting cuproptosis and disulfidptosis in cancer treatment. We highlight the complexity and dual roles of metabolic cell death in cancer and offer our perspective on how to leverage these cell death processes to develop innovative, targeted cancer therapies.

Epithelial-to-mesenchymal transition (EMT) is a cellular process during which cells lose their epithelial characteristics and acquire mesenchymal features with enhanced migration capacities. EMT has key roles in different aspects of tumorigenesis, including tumour initiation, progression, metastasis and resistance to therapy. Here, we have reviewed the recent advances in our understanding of EMT in cancer. Instead of being a binary switch as initially proposed, EMT has been shown to be composed of multiple tumour states residing in specific niches with distinct functional properties that are controlled by different gene regulatory networks. We discuss how the types of oncogenic mutations, signalling pathways, transcription factors, epigenetic regulators and microenvironmental cues regulate the different EMT states. We also highlight the mechanisms by which EMT controls resistance to anticancer therapy and how new approaches to pharmacologically target EMT in clinical settings have recently been developed.