Cytokines are promising therapeutic agents for cancer due to their immune-stimulating properties. However, their clinical application is limited by a narrow therapeutic window and dose-limiting on-target, off-tumor toxic...Cytokines are promising therapeutic agents for cancer due to their immune-stimulating properties. However, their clinical application is limited by a narrow therapeutic window and dose-limiting on-target, off-tumor toxicity. Advances in protein engineering enable the selective delivery of cytokines to the tumor microenvironment (TME) and antigen-specific T cells, enhancing antitumor efficacy while reducing systemic side effects. This review focuses on selected cytokines and outlines their developmental trajectory for treating solid tumors. We highlight strategies for constructing cis-signaling immunocytokines and procytokines for precise delivery to tumor sites and discuss the biological mechanisms through which these cytokines reactivate antitumor immunity. We also discuss the challenges and future directions for creating more effective cytokine-based therapeutics.
De Santis A, Zhu L, Tao J
… +2 more, Reißfelder C, Schölch S
Trends Mol Med
· 2025 Aug · PMID 39955217
·
Publisher ↗
Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small duct (SD-iCCA). These subtypes exhibit significant molecular, genetic, and histopathological differences...Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small duct (SD-iCCA). These subtypes exhibit significant molecular, genetic, and histopathological differences that impact patient prognosis and treatment responsiveness. This review advocates for a subtype-specific approach to iCCA research and clinical management, including tailored therapeutic strategies that consider distinct genetic profiles and tumor microenvironments. Current therapeutic approaches hold promise, yet efficacy varies by subtype. Additionally, subtype-specific molecular diagnostics, including DNA methylation-based classifiers and transcriptomic sequencing, have shown potential in refining iCCA subclassification, thereby guiding precision medicine efforts. This article outlines existing clinical trials, key research trajectories, and future directions for developing more effective subtype-adapted therapies for iCCA.
The advent and refinement of state-of-the-art spatial biology technologies have facilitated analysis that combines the advantages of high-throughput single cell analysis with techniques that preserve tissue architecture....The advent and refinement of state-of-the-art spatial biology technologies have facilitated analysis that combines the advantages of high-throughput single cell analysis with techniques that preserve tissue architecture. This combination of cellular phenotyping with retained spatial context provides a much greater understanding of cellular interactions within the tumour microenvironment (TME). For glioblastoma, with its significant intra-tumoural heterogeneity, cellular plasticity, and complex TME, appreciating and understanding these spatial patterns may prove key to improving patient outcomes. This review examines the advances in spatial biology techniques, discusses how these methodologies are being applied to study glioblastoma, and explores how spatial information improves understanding of the TME. Ultimately, it is this spatial context that will accelerate the identification of more effective treatments for glioblastoma.
Trends Mol Med
· 2025 Aug · PMID 39934021
·
Publisher ↗
Human cells potentiate highly diverse functions through tight transcriptional regulation and maintenance of genome integrity. While the DNA damage response (DDR) safeguards the genome, ligand-activated transcription fact...Human cells potentiate highly diverse functions through tight transcriptional regulation and maintenance of genome integrity. While the DNA damage response (DDR) safeguards the genome, ligand-activated transcription factors, such as steroid hormone receptors (SHRs), provide complex transcriptional outputs. Interestingly, an increasing body of evidence reveals a direct biological and functional interplay between DDR factors and SHR cascades in cancer. SHRs can directly affect DDR gene expression, but DDR factors in turn act as transcriptional coregulators, enabling oncogenic SHR-mediated signaling, which has the potential for novel therapeutic interventions. With a focus on breast and prostate cancer, we describe in this review recent developments in, and insights into, the complex interplay between SHR signaling and the DDR, highlighting opportunities for future clinical interventions.
Henshey B, Carneiro A, Lei K
… +2 more, Schaffer D, Boulis NM
Trends Mol Med
· 2025 Apr · PMID 39890493
·
Full text
Neurofibromatosis type 1 (NF1) is an inherited genetic disease resulting from pathogenic mutations in NF1 that drive tumor formation along peripheral nerves, leading to many functional consequences. Tumor removal or trea...Neurofibromatosis type 1 (NF1) is an inherited genetic disease resulting from pathogenic mutations in NF1 that drive tumor formation along peripheral nerves, leading to many functional consequences. Tumor removal or treatment often results in regrowth and/or nerve damage. Addressing NF1 pathogenic variations at the cellular level through gene therapy holds great potential for long-term treatment of patients with NF1. Adeno-associated viruses (AAVs) are broadly used gene delivery vehicles for gene therapies because of their low pathogenicity, ability to transduce nondividing cells, and potential for long-term gene expression. This article explores the landscape of AAV-mediated gene delivery strategies for NF1, discusses the challenges of efficient delivery to relevant cell types, and highlights the progress in vector design strategies.
Trends Mol Med
· 2025 Aug · PMID 39884873
·
Full text
Sex differences in immune system aging significantly impact disease susceptibility and vaccine responses among older adults, but with notable disparities between men and women. This area has gained importance because vac...Sex differences in immune system aging significantly impact disease susceptibility and vaccine responses among older adults, but with notable disparities between men and women. This area has gained importance because vaccines can exhibit differential efficacy by sex in aging populations, underscoring the need for sex-specific strategies. As the global population ages, understanding these sex-based immune differences is crucial for developing targeted interventions for age-related diseases. Addressing these disparities requires robust preclinical models that mimic human immune aging to uncover mechanisms and inform personalized approaches. In this review we assess the translational potential of preclinical mouse models in studying sex differences in immune aging, and emphasize the urgency of sex-specific interventions to improve health outcomes in older adults.
Trends Mol Med
· 2025 Aug · PMID 39875297
·
Publisher ↗
Ubiquitinylation of proteins regulates manifold processes and is reversed by deubiquitinylating enzymes (DUBs), which are therefore implicated in a plethora of cellular processes. DUBs are frequently upregulated in many...Ubiquitinylation of proteins regulates manifold processes and is reversed by deubiquitinylating enzymes (DUBs), which are therefore implicated in a plethora of cellular processes. DUBs are frequently upregulated in many diseases, while in a few cases downregulation of DUBs is associated with disease progression. This review focuses on the involvement of DUBs in the development and progression of gastrointestinal diseases with a particular emphasis on hepatic steatosis and hepatocellular, cholangio-, esophageal, gastric, colorectal, and pancreatic ductal carcinomas. In addition, pathogens that trigger the activity of several DUBs and thus suppress the immune response and cell survival are discussed. Finally, we highlight recent approaches made towards the therapeutic treatment of gastrointestinal diseases using DUB inhibitors.
Yu Q, Zhang Z, Herold F
… +15 more, Ludyga S, Kuang J, Chen Y, Liu Z, Erickson KI, Goodpaster BH, Cheval B, Pindus DM, Kramer AF, Hillman CH, Liu-Ambrose T, Kelley KW, Moon HY, Chen A, Zou L
Regular physical activity (PA) is beneficial for cognitive health, and cathepsin B (CTSB) - a protease released by skeletal muscle during PA - acts as a potential molecular mediator of this association. PA-induced metabo...Regular physical activity (PA) is beneficial for cognitive health, and cathepsin B (CTSB) - a protease released by skeletal muscle during PA - acts as a potential molecular mediator of this association. PA-induced metabolic and mechanical stress appears to increase plasma/serum CTSB levels. CTSB facilitates neurogenesis and synaptic plasticity in brain regions (e.g., hippocampus and prefrontal cortex) that support performance in specific cognitive domains including memory, learning, and executive function. However, the evidence regarding the role of PA-induced changes in CTSB as a mediator of PA-induced cognitive health in humans is mixed. To guide future research, this article identifies key factors that may explain the observed heterogeneity in the findings from human studies and proposes a PA-CTSB-cognition model.
Trends Mol Med
· 2025 Oct · PMID 39843289
·
Publisher ↗
Biological sex strongly impacts tuberous sclerosis complex (TSC) symptoms like epilepsy and autism. However, the mechanisms driving this influence remain largely unknown. Here, we discuss how sex-specific changes in brai...Biological sex strongly impacts tuberous sclerosis complex (TSC) symptoms like epilepsy and autism. However, the mechanisms driving this influence remain largely unknown. Here, we discuss how sex-specific changes in brain synapses and neural networks may drive these differences, offering insights that could be crucial for developing targeted therapies for TSC.
Trends Mol Med
· 2025 Aug · PMID 39814640
·
Publisher ↗
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that represents a significant public health challenge worldwide. This multifactorial condition results from complex interactions among genetic, environm...Inflammatory bowel disease (IBD) is a chronic inflammatory disorder that represents a significant public health challenge worldwide. This multifactorial condition results from complex interactions among genetic, environmental, immune, and microbial factors. Some beneficial microbes, known as probiotics, have been identified as promising therapeutic agents for inflammatory conditions, such as IBD. In this review, we explore the potential of probiotics as a therapeutic strategy for managing IBD. Probiotics have shown promise due to their ability to modulate the gut microbiota, regulate histamine levels, and enhance vitamin D metabolism, thereby promoting a tolerant immune profile and reducing inflammation. While the exact mechanisms underlying these benefits remain incompletely understood, probiotics represent a novel and emerging approach for alleviating the exacerbated inflammation characteristic of this disorder.
Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therape...Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival. These therapies - with distinct mechanisms, routes of administration, dosing schedules, side effect profiles, and financial costs - have dramatically altered the clinical phenotypes of this condition and have presented fresh challenges for patient care. In this review article we discuss potential strategies to maximise clinical outcomes through early diagnosis and treatment, optimised dosing, use of therapeutic combinations and state-of-the-art physiotherapy techniques, and the development of innovative therapies targeting alternative mechanisms.
Beta-thalassemia is a severe, hereditary blood disorder characterized by anemia, transfusion dependence, reduced life expectancy, and poor quality of life. Allogeneic transplantation of hematopoietic stem cells (HSCs) is...Beta-thalassemia is a severe, hereditary blood disorder characterized by anemia, transfusion dependence, reduced life expectancy, and poor quality of life. Allogeneic transplantation of hematopoietic stem cells (HSCs) is the only curative treatment for transfusion-dependent β-thalassemia, but a lack of compatible donors prevents the use of this approach for most patients. Over the past 20 years, the rise of gene therapy and the development of lentiviral vectors and genome-editing tools has extended curative options to a broader range of patients. Here, we review breakthroughs in gene addition- and genome-editing-based therapies for β-thalassemia, the clinical outcomes enabling approval by regulatory agencies, and perspectives for further development.
Bilirubin reductase (BilR), a gut microbiota-derived enzyme that reduces bilirubin to urobilinogen, was recently identified. Given the role of bilirubin in preventing modern diseases, understanding the link between the g...Bilirubin reductase (BilR), a gut microbiota-derived enzyme that reduces bilirubin to urobilinogen, was recently identified. Given the role of bilirubin in preventing modern diseases, understanding the link between the gut microbiota and health via modulation of bilirubin metabolism marks a major advance in medical research and potential treatments.
Alhumaidi R, Huang H, Saade MC
… +2 more, Clark AJ, Parikh SM
Trends Mol Med
· 2025 Jul · PMID 39757045
·
Full text
Disturbances in kidney tubular cell metabolism are increasingly recognized as a feature of acute kidney injury (AKI). In AKI, tubular epithelial cells undergo abnormal metabolic shifts that notably disrupt NAD metabolism...Disturbances in kidney tubular cell metabolism are increasingly recognized as a feature of acute kidney injury (AKI). In AKI, tubular epithelial cells undergo abnormal metabolic shifts that notably disrupt NAD metabolism. Recent advancements have highlighted the critical role of NAD metabolism in AKI, revealing that acute disruptions may lead to lasting cellular changes, thereby promoting the transition to chronic kidney disease (CKD). This review explores the molecular mechanisms underlying metabolic dysfunction in AKI, with a focus on NAD metabolism, and proposes several cellular processes through which acute aberrations in NAD may contribute to long-term changes in the kidney.
Trends Mol Med
· 2025 Mar · PMID 39755442
·
Publisher ↗
Seven primary familial brain calcification genes have been identified but their role in disease mechanisms has been less explored. Cheng et al. recently demonstrated that astrocyte-mediated regulation of brain phosphate...Seven primary familial brain calcification genes have been identified but their role in disease mechanisms has been less explored. Cheng et al. recently demonstrated that astrocyte-mediated regulation of brain phosphate (P) involves direct and functional interactions among three of these proteins, paving the way for new strategies to combat brain calcification.
Respiratory infections continue to pose a major global health challenge, leading to high morbidity and mortality. Effective vaccines are crucial for prevention of these, and nanotechnology offers a promising approach to...Respiratory infections continue to pose a major global health challenge, leading to high morbidity and mortality. Effective vaccines are crucial for prevention of these, and nanotechnology offers a promising approach to enhance vaccine efficacy through nanocarrier systems. This review explores recent advances in nanocarrier-based vaccines for respiratory pathogens, focusing on their ability to promote mucosal immunity against viral infections. It examines various types of nanocarriers, their physicochemical properties, and their role in improving vaccine delivery and immune responses. Additionally, the review examines key findings from both preclinical and clinical studies, highlighting the progress and challenges in developing nanocarrier vaccines for respiratory infections. These insights underscore the potential of nanotechnology to transform vaccine strategies and address unmet needs in respiratory disease prevention.