Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of 1:3,000. Pathogenic germline variants in the NF1 gene result in loss of the NF1 gene product, neurofibromin, which leads to hyperactivation of the RAS and other signaling pathways and tumorigenesis. A hallmark feature of NF1 is the development of peripheral nerve sheath tumors (PNSTs) ranging from histologically benign plexiform neurofibromas (PNs) to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), which lack effective medical therapies. Preclinical–clinical collaborations have led to substantial progress in the understanding of the biology and natural history of PNSTs. This has resulted in regulatory approvals of a targeted therapy, MEK inhibitors, for NF1 PNs. In addition, genomic studies and the development of liquid biomarkers have elucidated the evolution of PNs to MPNSTs, offering opportunities for earlier diagnosis and the development of prevention and therapeutic strategies.
A continuous rise in cancer incidence highlights the urgent need for innovative approaches to detect, diagnose, and treat this disease, while maintaining the quality of life for cancer patients. The circadian rhythm governs a broad spectrum of cellular processes, and its disruption has been linked to cancer development and metastasis. Consequently, circadian biology has emerged as a promising avenue for uncovering vulnerabilities and developing strategies to tackle cancer and its spread. In this review, we explore how circadian disruption impairs cellular homeostasis and affects carcinogenesis. We also examine the bidirectional relationship between the circadian rhythm and metastasis, presenting how a localized cellular disturbance can evolve into a systemic, whole-body imbalance. Finally, we review recent chronotherapy trials and discuss how leveraging circadian biology could inform the development of more effective cancer treatments.
Li-Fraumeni syndrome (LFS) is a heritable highly penetrant cancer predisposition syndrome caused primarily by germline pathogenic variants in the TP53 tumor suppressor gene. Individuals with LFS have a lifetime cancer risk approaching 100% and a broad phenotypic heterogeneity in age of onset and tumor subtype. Advances in our understanding of TP53 biology and the broad phenotypic spectrum have enhanced our insight into genotype–phenotype correlations in LFS. The role of surveillance and early detection has been crucial to improving the outcomes of those living with LFS; however, prevention and tumor interception are emerging as the next step to focus on in future studies. This review discusses the broad phenotypic spectrum of LFS, genotype–phenotype correlations, the biology of TP53 , early detection through clinical surveillance, and newborn screening as the next frontiers of cancer prevention and early cancer interception.
Vascular endothelial cells (ECs) within the tumor microenvironment (TME) function as active signaling hubs, not just passive conduits for nutrients. They secrete angiocrine factors that regulate cancer growth, metastasis, and response to therapy. These cells, specifically immunomodulatory ECs (iMECs), act as immune gatekeepers by directly interacting with and influencing immune cell function. This review examines how the angiocrine niche contributes to therapeutic resistance by modulating the immune landscape. We delineate key iMEC states that dictate the TME's immunological state, from an immune-responsive hot niche to a treatment-resistant cold state. These phenotypes include signatures that facilitate lymphocyte homing (HEV-like), recruit effector T cells (IFN-like), enable antigen presentation, and secrete distinct chemokine and cytokine profiles. Furthermore, we discuss how therapeutic interventions can induce EC senescence and alter angiocrine signals, thereby promoting therapy resistance. Understanding these complex EC–immune interactions is crucial for developing novel strategies to target the angiocrine axis and improve patient outcomes.
Cell polarity is the asymmetric localization of key membranes, proteins, and organelles needed for optimal cell function. Polarity is intrinsic to single cells but can also be influenced by external environmental cues, such as neighboring cell contacts in epithelia and the extracellular matrix. Given that most solid tumors arise from epithelia, it may not be surprising that defects in polarity are frequently noted in cancer formation and progression. In this review, we examine how cell polarity, an essential cornerstone of epithelial function, depends on reinforced cell–cell contacts as epithelia reach homeostatic densities and how its dysregulation can contribute to epithelial dysplasia and cancer. As cell extrusion, an essential driver of epithelial apoptosis conserved in all epithelioid tissues, acts as a vital tumor suppressor, we also investigate how this prodeath pathway can be converted into a proinvasive pathway when polarity is misregulated.
Diffuse large B cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease. Molecular profiling studies in DLBCL have identified three distinct disease subtypes using gene expression profiling, whereas mutation analysis of tumors has identified at least six separate subtypes. Although each classifier predicts clinical responses to immunochemotherapy and targeted therapies, molecular profiling is not universally performed or uniformly implemented. In this review, we focus on the biology of the LymphGen algorithm defined genetic subtypes revealed by genomic, transcriptomic, and single-cell profiling. We highlight recent advances in understanding the major drivers of disease and discuss how different mutations promote common hallmarks of cancer that are vulnerable to precision medicine agents.
CD8 + T cells are central to effective antitumor immunity, yet in cancer, they often undergo progressive transcriptional, epigenetic, and metabolic reprogramming that leads to an exhausted state and limits current immunotherapy. A deeper understanding of the molecular mechanisms that govern CD8 + T cell differentiation and function within the tumor microenvironment is essential to overcome this barrier. This review outlines the current knowledge of the transcriptional and epigenetic programs that shape T cell heterogeneity in cancer and chronic infection, with a focus on the formation and maintenance of exhausted T cell subsets. We highlight how T cell–intrinsic factors such as transcription factors and chromatin regulators and extrinsic factors such as nutrient availability converge to influence T cell fate decisions and function, as well as how these are affected in cancer. Finally, we discuss emerging therapeutic strategies aimed at reprogramming the epigenome to restore T cell function, offering new avenues to enhance the efficacy and durability of cancer immunotherapy.
The Tracking Cancer Evolution Through Therapy (TRACERx) program represents the most comprehensive effort to characterize tumor evolution in real time. Through longitudinal, multiregion, and multiomic profiling of tumors—and particularly of non-small-cell lung cancer and clear cell renal cell carcinoma—TRACERx has illuminated the dynamic interplay between genetic, nongenetic, and (micro)environmental factors that drive cancer progression, immune evasion, and therapeutic resistance. A central insight from TRACERx has been that not all tumor evolution is genomic: Transcriptomic diversity, epigenetic alterations, RNA editing, and changes in cell–cell interactions also drive adaptation. Methodological innovations—including tumor-informed and ultrasensitive circulating tumor DNA assays, representative sequencing, and integrative immune–genomic analyses—have yielded biomarkers resistant to sampling bias and/or predictive of recurrence, metastasis, and treatment response. By demonstrating that intratumor heterogeneity is a key determinant of clinical outcome and revealing its molecular, transcriptional, and ecosystem-level drivers, TRACERx has established a framework for linking evolutionary dynamics to patient care. As both a scientific framework and a clinical paradigm, TRACERx demonstrates how adaptive, iterative research can refine evolutionary models, improve patient risk stratification, and inspire next-generation cancer evolution studies across malignancies.
Cancer dormancy refers to an asymptomatic stage in cancer progression that contains residual disease. Cancer cells can disseminate from early tumors even before they are detectable, from advanced tumors, and from other metastases. Thus, cancer dormancy is a collective phenomenon, composed of single dormant cells that stopped dividing, tumor mass dormancy where cell proliferation is balanced by cell death, and active micrometastases. Dormancy evolves with complex spatiotemporal dynamics across length scales (from cell-intrinsic to cell-extrinsic interactions and microenvironmental regulation up to the body-wide systemic level) and across timescales (from single dormant cells to dormant tumor masses and active micrometastases), each responding differently to fluctuating microenvironments. Here we review biological in vivo and clinical observations of breast cancer dormancy across scales in length and time. Next, we outline 3D bioengineered models in which these different spatial and temporal scales are considered. Finally, we discuss challenges and opportunities of incorporating patient-derived cells. Collective cell behavior is an important aspect in cancer progression and, as such, modeling dormancy across scales in length and time could open new avenues to help us understand and predict the transition to active metastatic growth.
CD4+ T cells, through their diverse functional subsets, play multiple roles in the immune response to cancer. While helper subsets are critical for the initiation and effector phases of antitumor immune responses, immunoregulatory subsets promote tumor growth through multiple mechanisms. Additionally, research investigating the underpinnings of successful immunotherapy points to a substantial involvement of CD4+ T cells. In this article, we examine the varied functions of CD4+ T cells in shaping immune responses to tumors and emphasize the need to more deliberately include CD4+ T cells in the design of cancer therapies.
This review describes recent developments in DNA-encoded library (DEL) technology, which has enabled transformative discoveries in cancer research. Successful DEL screening campaigns for cancer-relevant targets are described in detail to highlight the unique advantages of this technology compared to other hit-generation strategies. Moreover, recent developments in screening methods that have helped expand the DEL-addressable target space are described, and their implications for cancer research are emphasized. DEL screening campaigns targeting RNA and transcription factors are discussed, and various cell-based DEL evaluation methods for membrane proteins are compared and put into context. Finally, the use of DEL technology for the discovery of novel bifunctional degraders is presented. Overall, this article provides a comprehensive overview of key DEL discoveries that are expected to be of significant interest to cancer researchers and medicinal chemists working in the field of oncology.
While cancer looms large in the public and scientific minds, this can result in a quite narrow view of its range and manifestations. The centering of human clinical investigations and the popularity of mouse models leave many unaware of fascinating findings about cancer in other species. Comparative oncology shows that cancer can be found not just in mammals but widely across the tree of animals, a realization that broadens views of the disease in fundamentally important ways. Examples include protective mechanisms of cancer-resistant species, transmissible cancers, and questions about whether cancer risk is intrinsic to metazoan life. I highlight strong evidence for cancer in invertebrates, focusing on Drosophila , which not only show many hallmarks of cancer but also induce host responses mimicking those of human patients, including antitumor immunity. A wide-ranging study of cancer-bearing species enhances the potential for transformative advances in battling this ancient disease.
Metabolic plasticity is a defining hallmark of cancer cells, enabling them to adapt dynamically to fluctuating demands for energy, biosynthesis, and redox balance throughout tumor progression—from escaping oncogene-induced senescence (OIS) to rapid proliferation, local invasion, and distant metastasis. The selection of metabolic pathways is shaped not only by intrinsic cellular needs but also by extrinsic factors such as substrate availability within the tumor microenvironment (TME). Dysregulated metabolism, a hallmark of aging, creates unique metabolic landscapes characterized by altered nutrient levels (glucose, amino acids, lipids) and increased levels of reactive oxygen species and inflammatory metabolites. While an excess of certain nutrients (e.g., sugars and lipids) may facilitate OIS escape and tumor cell proliferation, other age-related metabolic stresses, such as oxidative damage, chronic inflammation, and nutrient depletion, drive cancer cells to switch toward an invasive phenotype, thereby promoting metastasis. Despite aging being the most significant risk factor for cancer, its influence on tumor cell metabolic and phenotypic plasticity remains incompletely understood. This review synthesizes current literature on how age-associated metabolic changes in the TME modulate cancer cell metabolism and enhance phenotypic plasticity to promote tumor progression. We emphasize unresolved mechanistic questions regarding how aging predisposes cancer cells to more aggressive behavior via metabolic remodeling and discuss potential therapeutic strategies targeting these age-specific vulnerabilities to improve outcomes in elderly cancer patients.
The field of cancer glycobiology aims to understand how aberrant glycosylation contributes to the development of cancer. While the significance of glycosylation to normal and pathological cellular functions is widely appreciated, the comprehensive identification of specific aberrant glycan epitopes in cancer and mechanistic understanding of their impact remain limited. In this review, we begin with a brief general background on glycosylation to orient cancer researchers to the field. We next focus on research showcasing the roles that glycosylation plays in cancer, with an emphasis on studies that draw evidence from both clinical samples and mouse models. Finally, we conclude with a brief discussion of the clinical implications of glycosylation research toward improving the diagnosis and treatment of cancer.
Genome editing technologies have given us the ability to manipulate a genome with unprecedented accuracy. In cancer research, these technologies have enabled precise cancer modeling in cells and in vivo and facilitated systematic efforts to identify cancer drivers and dependencies. This review examines the current landscape of genome editing technologies, with an emphasis on next-generation methods to engineer complex nucleotide and chromosomal alterations. We highlight key examples that illustrate how these technologies have provided fundamental insights into this disease, and we discuss new approaches that integrate genome editing with multiomic methods. Finally, we discuss recent efforts to translate these technologies into the clinic.
Cytokines represent a diverse group of soluble proteins that play crucial roles in mediating cellular communication in order to regulate cell fate, particularly in the context of the immune system. Because of their critical roles in controlling cell differentiation, proliferation, migration, activation, and survival, cytokines are heavily implicated in the development and progression, as well as in the prevention and clearance, of cancer. Using both native cytokines and engineered versions thereof, ongoing research in the cancer field endeavors to harness the antitumor activities of cytokines to develop targeted immunotherapies. This review surveys the biology of cytokines and their use in cancer treatment, covering several categories of cytokines, including interleukins, interferons, chemokines, growth factors, and hormones. Preclinical and clinical efforts with natural and engineered cytokines along with efforts to combine these molecules with other anticancer modalities are discussed, highlighting both the triumphs and challenges for these essential proteins in oncology applications.
Cancer cachexia is a complex metabolic syndrome characterized by involuntary weight loss, skeletal muscle atrophy, adipose tissue remodeling, anorexia, and systemic inflammation. Affecting up to 80% of patients with advanced cancer, it is associated with poor prognosis and lacks effective therapies. This review focuses on metabolic reprogramming occurring between organs, integrating recent mechanistic insights into cross talk between central and peripheral tissues. Key mediators, including CCL2, IL-6, LIF, and GDF-15, are discussed in the context of neuroimmune and metabolic pathways that drive tissue wasting. Particular attention is given to the CCR2/CCL2 axis, which mediates immune cell infiltration into the brain, liver, and tumors, contributing to anorexia, muscle loss, and hepatic dysfunction. Understanding these integrated interorgan pathways highlights potential therapeutic targets to preserve metabolic homeostasis, improve functional outcomes, and extend survival in patients with cancer-associated cachexia.
Mitochondrial oxidative phosphorylation (OXPHOS) is an ancient metabolic process that is increasingly recognized as an important player in cancer onset, progression, and treatment resistance. In this review, we highlight the diverse biological roles of OXPHOS beyond ATP synthesis, discuss ways in which these roles interface with tumorigenesis, and consider methods to measure and manipulate OXPHOS in cancer studies. Instead of the traditional view of OXPHOS as a linear pathway with a single, defined output (i.e., ATP), we propose a more granular model of OXPHOS as a collection of interrelated functional modules that are coupled to various extents in a context-dependent manner. As a case study, we apply this modular framework to examine links between OXPHOS function and cancer metastasis. This conceptual model of OXPHOS function will support ongoing work to dissect the complex—but ultimately understandable—contributions of OXPHOS to cancer phenotypes.
The concept of targeted delivery of anticancer agents using tumor-selective antibodies led to the evolution of antibody–drug conjugates (ADCs). Early efforts using traditional chemotherapy agents as ADC payloads were unsuccessful. The selectivity of antibodies was then leveraged to deliver potent cytotoxic agents that could not be administered systemically. The first two decades of exploration and approvals were with ADCs comprised of payloads that induce DNA damage (calicheamicins) or disrupt microtubule function (auristatins, maytansinoids) for treatment of both hematologic and solid tumor malignancies. More recently, ADCs with topoisomerase 1 inhibitor payloads have been successful for treating breast cancer and other solid tumors. Because ADCs show more toxicities than first anticipated, different approaches are under exploration for optimization of the antibody, linker, and drug components, with the goal of maintaining or increasing clinical activity while reducing associated toxicities. This review covers the history of ADC development, currently approved ADCs, and future efforts to improve ADC properties.
Imaging biological samples in three dimensions across scales is essential for capturing the complex spatial relationships that govern cancer initiation, invasion, and therapeutic response. As biological inquiry shifts from isolated molecular measurements toward spatially contextualized, multiomic profiling, new strategies have emerged to reconstruct tissue architecture at the whole-organ scale and subcellular resolution. These advances offer more anatomically faithful representations of tissue organization and open doors to integrating morphology with deep multiomic profiling in spatially resolved formats. As a result, we are improving our understanding of inter- and intratumoral heterogeneity and the key role of rare events and minority cell populations in tumor progression. The primary techniques used for 3D imaging of tumors include intact tissue imaging for targeted visualization of biological processes and serial sectioning for integration of diverse, multiomic platforms. In this review, we survey the major technologies used to image tumors in three dimensions, highlighting key methodologies, trade-offs, and recent innovations that make these approaches increasingly central to modern cancer research.
