Trends in Pharmacological Sciences

Cancer pathogenesis and phase targeting through condensate fragility Nuclear liquid–liquid phase separation (LLPS) is now recognized as a fundamental mechanism that organizes transcription and DNA repair machinery into dynamic, membraneless condensates essential for genome integrity and gene regulation. Dysregulated LLPS has emerged as a key driver of oncogenesis; yet, how pathological condensates simultaneously fuel transcriptional addiction and genomic instability remains incompletely understood. Recent biophysical and molecular advances, particularly in multivalency, concentration thresholds, and condensate material states, have revealed that cancer-associated mutations rewire phase behavior to generate hyperstable yet fragile condensates. This review explores the role of aberrant nuclear LLPS in cancer pathogenesis and therapy resistance and uniquely proposes phase targeting through condensate fragility as a precision oncology strategy, distinguishing itself by integrating oncogenic mechanisms with actionable biophysical vulnerabilities rather than focusing solely on molecular inhibition.

Cancer pathogenesis and phase targeting through condensate fragility

Macrophage heterogeneity and plasticity: mechanism and therapeutics Macrophages play pivotal roles in regulating immune responses during inflammation and cancer. Recent evidence indicates that macrophages are dynamic cells capable of switching between different functional states in response to stimuli from their local microenvironment. However, characterizing these functional states in the context of inflammation and cancer has been challenging due to a lack of powerful tools. To address this important issue, recent studies have employed single-cell technologies and emerging immunoinformatics methods to explore the relationship between macrophage phenotypic states and their cellular functions. Here, we synthesize insights from these studies and discuss the current understanding of macrophage diversity (heterogeneity) and adaptability (plasticity) in acute inflammation, chronic diseases, and cancer. We also highlight the molecular mechanisms that initiate macrophage state transitions during disease progression. By integrating knowledge gained from different disease models, we propose a conceptual framework for the future development of pharmacological approaches aimed at targeting macrophages effectively.

Macrophage heterogeneity and plasticity: mechanism and therapeutics

Dynamics and heterogeneity of the neurovascular unit in ischemic stroke The neurovascular unit (NVU) is a multicellular system functioning to maintain healthy brain homeostasis and regulate the exchange of essential elements between the blood and the brain. Recent studies have shown that, in response to ischemic stroke (IS), the NVU undergoes dynamic structural remodeling and metabolic dysfunction, revealing new features of IS pathogenesis. Recent breakthroughs in single-cell multiomics provide emerging evidence regarding the spatiotemporal heterogeneity of NVU responses to IS. To date, clinical treatments for IS-induced brain injury remain very limited. These new studies have advanced our knowledge of the dynamic cellular and molecular changes of the NVU after IS, paving the way for new therapeutic strategies.

Dynamics and heterogeneity of the neurovascular unit in ischemic stroke

March 2026 issue first authors ‘Meet the first authors’ is a TrendsTalk series launched in Trends in Pharmacological Sciences in 2026 by Dr Jerry Madukwe, Editor-in-Chief of the journal. These articles feature the first authors of review and opinion articles published in each monthly issue. This series offers these authors a platform to share their personal perspectives on current challenges in the field, explore future directions for their research areas, and highlight opportunities for collaborations and new ventures they are eager to pursue.

March 2026 issue first authors

β-Arrestins and disease-linked variants: opportunities for targeted modulation

Attruby for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) STRUCTURE: Attruby, also known as acoramidis hydrochloride or AG10, is a synthetic small-molecule organic compound developed as a hydrochloride salt. Its chemical structure is designated as 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid hydrochloride, with a molecular formula of C15H18FN2O3·HCl and a molecular weight of 328.77 g/mol. The molecule features a 4-fluorobenzoic acid aromatic core linked through a propoxy ether chain to a 3,5-dimethyl-1H-pyrazole heterocycle. The structural formula is shown above.

Attruby for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM)

Leveraging conformational ensembles in allosteric drug discovery Proteins involved in signaling networks, such as Ras, mammalian target of rapamycin (mTOR), and epidermal growth factor receptor (EGFR), exist as dynamic conformational ensembles in biomolecular condensates. These ensembles play a crucial role in allosteric drug discovery and action. Traditional approaches in drug discovery often trace back to the induced fit model, which viewed proteins as rigid entities with active and inactive states. However, this model’s limitations hindered successful drug development. Advanced molecular dynamics simulations of oncogenic mutants and experiments reveal heterogeneous dynamic ensembles, which can uncover targetable spots like cryptic pockets and cooperative exosites that only exist transiently. In this review, we clarify traditional dogmas and show how recent knowledge improves allosteric drug design by leveraging conformational ensembles, with examples. We further discuss how ensemble-based approaches can advance promising therapeutics, unlocking their potential for more effective future strategies, including in biomolecular condensates.

Leveraging conformational ensembles in allosteric drug discovery

Targeting metabolic vulnerabilities with advanced delivery systems Metabolism modulation has emerged as a promising frontier in precision oncology. Nonetheless, the primary gap is the inability to precisely target the unique metabolic vulnerabilities of different cell types in vivo, which has limited clinical translation. Recent strategies that integrate tumor metabolism with advanced delivery systems are now enabling targeted metabolic intervention. In light of these developments, we evaluate current progress and highlight a path forward for metabolism-modulating drug delivery systems (MDDSs) in precision oncology. We also dissect key translational barriers—including metabolic heterogeneity, biological barriers, and off target effects—and discuss challenges in preclinical validation and clinical translation. Moreover, we propose emerging solutions—including metabolic circuit mapping, artificial intelligence-driven carrier design, and integrated MDDS platforms—to further advance the development of precision metabolism-based therapeutics.

Targeting metabolic vulnerabilities with advanced delivery systems

Palmitoyl-protein thioesterase-1 in health and disease

Evolving paradigms in targeting FLT3 for acute myeloid leukemia therapy FLT3 mutations drive acute myeloid leukemia (AML) progression through aberrant signaling, making FLT3 inhibition a key therapeutic strategy. Current inhibitors show efficacy, yet resistance and toxicity remain challenges. Emerging approaches, including selective inhibitors, proteolysis-targeting chimeras, and protein degraders, offer enhanced potency, sustained suppression, and combinatorial potential, representing a precision-based advancement in AML treatment.

Evolving paradigms in targeting FLT3 for acute myeloid leukemia therapy

Targeted alpha therapy (r)evolution: emerging nuclides for clinical applications Targeted alpha therapy (TAT) delivers localized, high linear energy transfer (LET) radiation that induces irreparable DNA damage, particularly double-strand breaks, leading to selective tumor cell death. Alpha emitters are gaining interest due to their potent efficacy and favorable safety profiles compared with conventional treatments. Advances in chelator design have enabled the formation of highly stable chelating complexes or covalent binding to targeting molecules. Actinium-225, astatine-211, and lead-212 are the most promising and clinically advanced alpha-emitting radionuclides. However, scaling up production and ensuring a sustainable global supply remain major challenges. This review highlights recent progress in radionuclide production, radiochemistry, chelator development, and tumor-targeting strategies and examines the current landscape of clinical trials involving these three alpha emitters.

Targeted alpha therapy (r)evolution: emerging nuclides for clinical applications

The February issue of Cell Press Trends in Pharmacological Sciences is online now

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February 2026 issue first authors Meet the First Authors is a TrendsTalk series launched in Trends in Pharmacological Sciences in 2026 by Dr Jerry Madukwe, Editor-in-Chief of the journal. These articles feature the first authors of reviews and opinion articles published in each monthly issue. The series offers a platform for authors to share their journey to becoming scientists, their current roles and sources of inspiration, personal perspectives on current challenges in their field, and their thoughts on future research directions.

February 2026 issue first authors

I am especially grateful to all the authors who proposed these covers. If you have a review idea, we would love to hear from you—and look forward to publishing your work in 2026!

Happy New Year to the authors, peer reviewers, and readers of Cell Press Trends in Pharmacological Sciences.

In 2025, our covers featured insightful articles on emerging therapeutic targets, mechanisms of action, biologics, immunotherapy, and more.

Targeting peptide–HLA complexes for precision immunotherapy Precision immunotherapy leverages the immune system to selectively eliminate abnormal cells while sparing healthy cells. Targeting specific peptide–human leukocyte antigen (pHLA) complexes, derived from cancer, autoimmune, and infectious disease, enables precise intervention, because these antigens are minimally expressed in normal tissues. However, designing binders with high specificity and low cross-reactivity remains challenging. Inspired by natural T cell receptor (TCR) recognition of pHLA complexes, synthetic approaches, including TCR-mimic antibodies (TCRm) and de novo pHLA binders, are emerging, adaptable into T cell engagers and adoptive therapies with promising specificity and efficacy. Moreover, advances in artificial intelligence (AI)-driven methods, immunopeptidomics, and computational protein design are accelerating the discovery and pan-allelic development of highly specific pHLA therapeutics. In this review, we discuss current approaches, mechanisms, preclinical and clinical data, and cutting-edge technologies shaping the future of pHLA-targeted immunotherapies.

Targeting peptide–HLA complexes for precision immunotherapy

Therapeutic antibodies targeting G protein-coupled receptors G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are involved in numerous physiological and pathological processes. Therapeutic antibodies targeting GPCRs, including monoclonal antibodies (mAbs), single-domain antibodies (sdAbs), and antibody–drug conjugates (ADCs), represent a promising class of biologics with high specificity and therapeutic potential. The integration of innovative screening technologies, structural biology, and computational approaches has significantly accelerated the discovery of antibody-based therapeutics against GPCRs. In this review, we discuss the emerging strategies used in the development of these therapeutic antibodies, examine key insights from pathogenic autoantibodies, evaluate the clinical trial landscape, and explore how emerging technologies such as artificial intelligence (AI)-assisted design and membrane-mimetic systems are driving the next generation of GPCR-targeted therapeutics.

Therapeutic antibodies targeting G protein-coupled receptors

Blujepa for the treatment of uncomplicated urinary tract infections STRUCTURE: Blujepa tablets contain gepotidacin mesylate, a triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV. The chemical name is (R)-2-((4-(((3,4-dihydro-2H-pyrano[2,3-c]pyridin-6-yl)methyl)amino)piperidin-1-yl)methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione methanesulfonate dihydrate. The molecular formula is C24H28N6O3-CH4O3S-2H2O and its molecular mass is 580.66. The structural formula is shown in the top figure.

Blujepa for the treatment of uncomplicated urinary tract infections

January 2026 issue first authors ‘Meet the first authors’ is a TrendsTalk series launched in Trends in Pharmacological Sciences in 2026 by Dr Jerry Madukwe, Editor-in-Chief of the journal. These articles feature the first authors of review and opinion pieces published in each monthly issue. The series offers a platform for authors to share their journey to becoming scientists, their current roles and sources of inspiration, personal perspectives on current challenges in their fields, and their thoughts on future research directions.

January 2026 issue first authors

Introducing a new TrendsTalk series in TiPS This month, Trends in Pharmacological Sciences features a new TrendsTalk series, ‘Meet the first authors’. These articles feature the first authors of review and opinion pieces published in each monthly issue. The series provides a platform for authors to share their journey to becoming scientists, their current roles and sources of inspiration, personal perspectives on current challenges in their fields, and their thoughts on future research directions. It also highlights opportunities for collaborations, new ventures they are eager to pursue, and advice for younger scientists.

Introducing a new TrendsTalk series in TiPS

Targeting ion channel dysregulation in tumors: emerging therapeutic opportunities

Lipids as pharmacological targets in age-related lens disease Cataract and presbyopia are the leading causes of age-related vision impairment worldwide, yet non-surgical management options remain limited. Age-related changes in the lipid composition of the crystalline lens have been implicated in their pathophysiology, highlighting the lens lipidome as a potential therapeutic target. In this review we summarize how recent advances in high-resolution and spatial lipidomics have clarified age- and region-specific changes in the lens lipidome, and we evaluate recent research efforts to utilize topical lipid-replenishing formulations and lipid-modifying small molecules to reverse these changes. We outline challenges in drug delivery to the avascular and encapsulated lens, and highlight how emerging technologies such as nanoparticles may overcome barriers to lens penetration, providing a path toward a pharmacological lens intervention.

Lipids as pharmacological targets in age-related lens disease

PDE4 modulates muscle signaling in cancer cachexia The bioenergetic crisis in cancer cachexia arises from early mitochondrial dysfunction that precipitates muscle wasting. In a recent study, Angelino et al. found that tumor-derived signals suppress the cAMP-protein kinase A (PKA)-CREB1 axis, destabilizing mitochondrial homeostasis. Restoring cAMP signaling through phosphodiesterase 4 (PDE4) inhibition rescued mitochondrial function, highlighting a promising strategy to mitigate tumor-induced cachexia.

PDE4 modulates muscle signaling in cancer cachexia

Treating periodontal disease: from antimicrobials to immunomodulation

Siglecs in immunotherapy: current clinical landscape and prospects Siglecs are a family of sialic acid-binding immunoglobulin-like lectins that regulate immune signaling and maintain homeostasis through glycan recognition. Despite their central role in immune modulation, their therapeutic potential remains underexplored. Advances in antibody engineering, glycan biology, and molecular design have greatly expanded our understanding of Siglec–ligand interactions, revealing their promise in regulating immunosuppression in cancer and autoimmunity. The current clinical landscape shows trials targeting mainly Siglec-2 and -3, with a predominant focus on hematological cancers. This review evaluates preclinical and recent clinical progress in Siglec-targeted immunotherapies, emphasizing mechanisms, safety, and efficacy, and proposes a translational framework to accelerate therapy development and broader immunotherapy advancements.

Siglecs in immunotherapy: current clinical landscape and prospects

Nerandomilast as the first PDE4B-selective therapy in idiopathic pulmonary fibrosis STRUCTURE: Nerandomilast is a small-molecule thienopyrimidine sulfoxide derivative that contains a thieno[3,2-d]pyrimidin-5-one core substituted with a (5-chloropyrimidin-2-yl)piperidinyl group and an (R)-hydroxymethyl-cyclobutylamino side chain. This structural arrangement confers high affinity and selectivity for the PDE4B isoform while minimizing off-target inhibition of other PDE4 subtypes. The sulfoxide (S) stereochemistry and the (5R) configuration at the cyclobutyl center are essential for PDE4B selectivity.

Nerandomilast as the first PDE4B-selective therapy in idiopathic pulmonary fibrosis

Targeting androgen receptor signaling to enhance cancer immunotherapy Men experience higher cancer incidence and mortality than women, and accumulating evidence implicates androgen receptor (AR) signaling as a key biological driver of these sex-based disparities. AR signaling can suppress adaptive anticancer immunity. Preclinical studies across multiple cancer types show that AR inhibition enhances T cell function and sensitizes tumors to immune checkpoint inhibition. However, recent Phase 3 trials combining AR suppression with immune checkpoint blockade in prostate cancer (PCa) failed to demonstrate clinical benefit. We discuss these developments and summarize recent studies defining the role of AR signaling in anticancer immunity. We propose strategies to translate emerging insights into rational trial designs that optimize the integration of AR suppression with immunotherapy.

Targeting androgen receptor signaling to enhance cancer immunotherapy

Molecular glues evolve from serendipity to rational design Molecular glues (MGs) modulate protein interactions to inhibit, activate, or degrade targets. Classical MGs like thalidomide, cyclosporin, and fusicoccin were discovered serendipitously; a key challenge is to develop rational design approaches for MGs. Recent advances in knowledge of the structure–activity relationships (SAR) of MGs have resulted in rational design of new MGs. Moreover, newer structure-based design technologies have increased the target diversity of preclinical MGs and multiple candidates are in clinical trials. Here, we highlight the evolution of MGs from natural products to synthetic compounds and discuss integration of emerging technologies to inform their rational design into new therapeutic agents.

Molecular glues evolve from serendipity to rational design

Sodium's role and therapeutic targeting in cancer Cancer cells exhibit unique metabolic reprogramming characterized by a significant increase in intracellular sodium ion levels. Sodium influences cancer cell metabolism, immune function, and drug resistance, and can trigger a unique cell death pathway when overloaded. Sodium-related transporters regulate cellular sodium ion levels and cancer progression. Targeting these transporters with specific inhibitors might therefore be an effective way to treat cancer. However, the precise relationship between sodium and cancer cell behavior is insufficiently studied and our understanding of the relevant transporters remains inadequate. In this review we summarize current understanding of the role of sodium in cancer. We analyze the impact of sodium-related transporters on cancer and current therapeutic strategies that target these transporters. We also highlight key challenges and discuss potential strategies for future investigations.

Sodium's role and therapeutic targeting in cancer

Transforming the drug discovery landscape Drug discovery and development is a complex, multi-stage process involving target identification and validation, lead compound discovery, mechanism of action elucidation, efficacy and toxicity evaluation, followed by clinical testing and regulatory approval. Recent breakthroughs have begun to overcome longstanding bottlenecks across this pipeline – particularly in membrane-targeted therapy, psychedelic drug, and RNA-based medicine discovery research. Moreover, the increasing role of artificial intelligence (AI) in tumor-targeted antibody drug conjugate (ADC) and rare disease drug discovery cannot be ignored.

Transforming the drug discovery landscape