Head and neck squamous cell carcinoma (HNSCC) is a biologically complex malignancy in which durable responses to standard multimodal therapies, targeted therapies, and immune checkpoint inhibitors remain limited. Therapeutic resistance arises from interconnected oncogenic signaling, tumor plasticity, heterogeneity, and immune evasion, which enable tumors to bypass inhibition of individual pathways. These mechanisms also differ across biologically distinct HNSCC subsets, including human papillomavirus (HPV)-positive and HPV-negative disease. Emerging therapeutic platforms in preclinical and clinical development, including targeted protein degraders, engineered antibodies, cellular and vaccine-based immunotherapies, photoimmunotherapy, and epigenetic modulators, provide new opportunities to target these interconnected vulnerabilities. In this review, we examine how these pharmacological strategies may overcome resistance in HNSCC and discuss their integration into biomarker-guided, mechanism-driven combination regimens.

Immune checkpoint inhibitors have changed cancer management. However, immune-related adverse events (irAEs) can disrupt treatment and limit effective combination strategies. The standard of care tends to involve broad immunosuppression, which may compromise antitumor immunity and fail to address the dominant biology of distinct irAEs. Some evidence suggests that irAEs can be mitigated through mechanism-based interventions, including cytokine blockade, tissue-restricted immunomodulation, and strategies targeting pathogenic lymphocytes or humoral pathways. Emerging irAE biomarkers help support personalized risk assessment, diagnosis, and intervention selection. In this review, we examine key advances in targeted interventions and biomarkers and outline a translational and clinical path forward, ranging from clinically useful irAE taxonomies to biomarker-guided trials, to advance precision toxicity control toward clinical practice.

Antimetabolites have been used to treat cancer since the 1950s, yet how tumors survive remains unclear. Two studies by Moss and colleagues and Witus and colleagues show that surviving cells recycle nucleotides and reshape mitochondria, revealing a shared resistance program. Because this program is measurable, it could identify, before treatment, which patients would benefit from drugs that block it.

Immune checkpoint blockade has revolutionized cancer therapy, but durable benefit remains limited by immune-cold tumor states, poor antigen presentation, T cell exhaustion, and adaptive resistance. Recent studies position lysine-specific demethylase 1 (LSD1) as a druggable epigenetic regulator that links these barriers across tumor and immune cells. Emerging evidence shows that targeting LSD1 can restore major histocompatibility complex class I antigen presentation, activate viral mimicry and interferon programs, modulate programmed death-ligand 1 in a context-dependent manner, influence CD8+ T cell state transitions, and restrain tumor plasticity. In this review, we feature these mechanistic advances, compare evolving drug classes, and outline biomarker-guided strategies that may support the rational development of next-generation combination immunotherapy.

A α-helical conformation within Class B1 G protein-coupled receptors agonists has been thought necessary for receptor activation. Gellman et al. suggested that selective replacement of L-amino acids with D-enantiomers could yield biased agonists. The new strategy helical would broaden the tools available for investigating agonist conformations and therapeutic potentials.

Astrocytes remove extracellular α-synuclein aggregates through p62-dependent autophagy, yet the factors limiting this defense remain unclear. Zhang and colleagues recently identified cholesterol 25-hydroxylase as an inducible negative regulator of p62-mediated clearance. Genetic suppression or a p62-derived decoy peptide reduced α-synuclein pathology in mouse models of Parkinson’s disease.

Synapse loss is a defining feature of neurodegenerative disease, yet the signals that orchestrate synaptic elimination remain incompletely understood. Crowley and colleagues uncover an unexpected link between neuronal hyperactivity and adaptive immunity, showing that antibody-secreting B cells and immunoglobulins can drive complement-dependent synapse loss.

Lipid droplet (LD) accumulation in neurons and glia is a feature of Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) and is associated with oxidative stress and neuroinflammation. Although protein-targeted monotherapies have achieved partial clinical success, continued disease progression in many patients suggests that additional cellular mechanisms contribute to pathogenesis. Lipophagy, the selective autophagic degradation of LDs, provides a potential clearance route but has been studied primarily in hepatocytes under nutrient deprivation. Recent studies have begun to map noncanonical regulatory mechanisms of lipophagy, identify disease-associated points of failure in AD, PD, and ALS, and report compounds that enhance LD clearance through mechanisms distinct from canonical nutrient sensing. In this article, we review these advances and discuss the emerging rationale for exploring neuron- and context-specific approaches to modulate lipophagy as a complementary strategy in neurodegeneration.

Artificial intelligence (AI) not only accelerates drug discovery but also creates regulatory gaps—with more than 100 AI-assisted pipelines in trials. Frameworks lack enforceable standards. We propose a risk-tiered framework that distinguishes discovery AI from evidence-generating AI, mandates impact assessments and Investigational New Drug disclosure when AI influences decisions, and transforms guidelines into binding, risk-proportionate regulation.

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.

Targeting the orthosteric site of G protein-coupled receptors (GPCRs) has long dominated drug discovery, but intracellular allosteric modulators (AMs) provide new avenues to enhance selectivity and fine-tune signaling. Recent structural advances have illuminated intracellular allosteric pockets that act as conformational control hubs for transducer-selective engagement, biased signaling, and noncanonical receptor activation. Among these, the transmembrane helix 3 (TM3)–intracellular loop 2 (ICL2)–TM4 intracellular pocket (hereafter, the ICL2 site) has emerged as a key determinant of GPCR signaling bias and a strategic target for intracellular AM development. We review emerging structure–activity relationships, mechanistic and evolutionary determinants of ICL2-targeted intracellular allostery, and key translational challenges including membrane accessibility, pharmacokinetics, and species divergence. Finally, we highlight structure-guided and affinity-based discovery strategies for engineering pathway-selective intracellular AMs with greater transducer control than conventional orthosteric ligands.

Targeted protein degradation has emerged as a powerful way to eliminate disease-driving proteins rather than merely inhibit them. However, most current approaches depend on ubiquitin ligases, whereas midnolin bypasses E3 recruitment and substrate ubiquitination while converging on the same 26S proteasome used for canonical ubiquitin-dependent degradation. Recent structural, biochemical, and disease studies have defined how midnolin recognizes β-strand-forming degrons, positions substrates at the 26S proteasome, and contributes to interferon regulatory factor 4 regulation, while engineered midnolin-targeting chimeras and midnolin-based targeting chimeras have redirected this pathway toward β-catenin and c-Myc. By linking endogenous pathway biology with engineered degrader pharmacology, this review compares midnolin-directed degradation with proteolysis-targeting chimeras and molecular glue degraders and identifies the design, delivery, and safety principles that will determine whether it becomes a useful ubiquitin-independent complement to existing degraders.

STRUCTURE: Centanafadine (EB-1020, CTN), also known as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a norepinephrine (NE)-preferring triple [NE–dopamine (DA)–serotonin (5-HT)] reuptake inhibitor. The free base has a molecular formula of C15H15N and a molecular weight of 209.3 g/mol; the drug is formulated as the hydrochloride salt (C15H15N·HCl, 245.7 g/mol). The molecule consists of a 3-azabicyclo[3.1.0]hexane core bearing a naphthalen-2-yl group at position 1, with (1R,5S) stereochemistry.

Mitochondrial quality control is essential for maintaining cellular and tissue homeostasis. Mitophagy, the selective autophagic removal of damaged mitochondria, is a central component of this process, and defects in mitophagy are increasingly linked to neurodegeneration, cardiovascular disease, cancer, and inherited mitochondrial disorders. Ubiquitin-dependent tagging of outer mitochondrial membrane proteins is a major mechanism for marking damaged mitochondria for clearance; however, recent advances reveal that mitochondrial deubiquitinases (DUBs) shape ubiquitin signaling at damaged mitochondria, thereby influencing the efficiency and selectivity of mitochondrial turnover. Moreover, DUBs are emerging as context-dependent editors of the mitochondrial ubiquitin code that link mitophagy to disease pathogenesis and therapeutic intervention. Here, we synthesize current understanding of mitochondrial DUBs in physiology and disease and discuss emerging pharmacological strategies to guide the development of mitophagy-targeted therapeutics.

Caspase inhibitors have repeatedly entered clinical trials but have not reached clinical practice due to toxicity and limited efficacy. Groborz and colleagues now show that gasdermin D pores admit otherwise membrane-impermeable inhibitors into pyroptotic cells, turning poor permeability into a mechanism of cell-state selectivity.

Drug discovery relies on cellular assays to determine whether a candidate produces a desired response, reveals its mechanism, or causes toxicity, but only a small fraction of compound–dose–time–context combinations can be measured experimentally. Recent perturbation atlases, single-cell and imaging technologies, and intervention-conditioned AI models now make prediction of unmeasured cellular responses a testable objective. AI virtual cells could therefore complement conventional discovery by prioritizing compounds, contexts, and follow-up experiments rather than replacing laboratory assays. Here, we review the resources and modeling advances supporting this capability, assess their value for mechanism-of-action analysis, efficacy, safety, resistance, and combination studies, and define evidence requirements for pharmacological use. Data coverage makes oncology, including immuno-oncology, plausible early proving grounds, with safety assessment as a crosscutting use case; broader deployment requires perturbation-specific, mechanistic, and decision-level validation.

Nitroxyl (HNO) donors enhance cardiac contraction and relaxation. However, systemic administration of these donors provides limited control over local HNO exposure or interaction with the target. This forum discusses recent approaches and challenges to control HNO generation, reshape exposure, and assess target engagement, evaluating mechanisms, maturity, constraints, and therapeutic fit.

Signal transducer and activator of transcription 1 (STAT1) is a central regulator of interferon signaling, antiviral defense, inflammation, and antitumor immunity. Although STAT1 activation has been traditionally defined by phosphorylation, recent studies have revealed diverse post-translational modifications (PTMs) that fine-tune its activity, stability, localization, and transcriptional output. Newly identified modifications, including vitamin C-derived vitcylation and pyruvate-induced pyruvylation, directly link nutrient and metabolic cues to STAT1 signaling. Additional PTMs, such as acylation, glycosylation, ubiquitination, methylation, and oxidative modifications, further shape STAT1 function in a context-dependent manner. In this review, we evaluate the evidence supporting STAT1 PTMs and discuss how specific modifications regulate STAT1 activation, stability, localization, and transcriptional output in immune and inflammatory contexts, while distinguishing established regulatory mechanisms from emerging modifications that require further validation.

Scientific disciplines routinely reassess methods but rarely the concepts guiding scientific reasoning. We identify three mechanisms of conceptual persistence: amnesia, institutionalisation, and reification—the process by which an operational construct is regarded as biological reality. These mechanisms may impede scientific self-correction, a challenge increasingly relevant as artificial intelligence learns from scientific literature.

Tumor-intrinsic voltage-gated Cav3 calcium channels, comprising the Cav3.1, Cav3.2 and Cav3.3 isoforms, have been implicated in cancer cell proliferation and survival. Recent work by Dube et al. reveals a role for microenvironmental Cav3.2 channels in glioblastoma, promoting neuron–cancer cell crosstalk and identifying changes in immune-related programs associated with Cav3.2 deficiency.

How Lewy pathology forms and diversifies remains a central question in Parkinson’s disease research. A recent study by Mahul-Mellier and Colleagues proposes a dynamic model in which inclusion maturation and organelle remodeling drive pathological heterogeneity, reshaping concepts of disease mechanisms and providing new perspectives on therapeutic approaches.

Biased agonism has emerged as a promising strategy for improving incretin therapeutics, yet the structural determinants of signaling bias remain incompletely understood. Building on their recent parathyroid hormone 1 receptor–β-arrestin structure, Zhao and colleagues identify extracellular loop 3 as a conformational switch controlling glucagon-like peptide-1 receptor transducer selectivity, enabling rational design of biased agonists.

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.

Oncolytic viruses hold immense therapeutic promise but face formidable systemic delivery barriers. A new study by Xu et al. engineered immunoglobulin E-sensitized mast cells to selectively ferry these viruses into tumors. Excitingly, antigen-triggered degranulation precisely releases the viral payload and reshapes the immune microenvironment, offering a highly modular delivery paradigm.

Pathological tau accumulation underlies a spectrum of neurodegenerative diseases collectively known as tauopathies. Although reducing tau remains the prevailing therapeutic strategy, indiscriminate tau reduction may compromise physiological functions and has demonstrated limited clinical efficacy. Growing evidence indicates disease- and stage-specific tau heterogeneity—spanning post-translational modifications (PTMs), aggregation states, and vulnerable cell populations—highlighting the necessity for improved targeting selectivity for pathological tau species. In this review, we discuss tau-targeting therapeutic modalities, including nucleic acids to suppress tau expression, immunotherapies and chimeric degraders to facilitate tau protein clearance, inhibitors of aggregation, and emerging strategies for tau PTM-editing and cellular-level interventions for neurofibrillary tangle-bearing neurons.

Glioblastoma (GBM) remains a devastating disease for which standard temozolomide chemotherapy is limited by O6-methylguanine–DNA methyltransferase (MGMT)-mediated DNA damage repair. By targeting epidermal growth factor receptor (EGFR), a major oncogenic driver of GBM, Guo, Habib, and colleagues demonstrate that EGFR inhibition prior to temozolomide treatment induces an adaptive response that downregulates MGMT, enhancing therapeutic efficacy.

Pain remains a major clinical challenge because current analgesics lack spatiotemporal precision and frequently induce systemic adverse effects, tolerance, and dependence. Recent advances in photopharmacology have enabled reversible optical control of ion channels, G protein-coupled receptors, and neural circuits involved in nociceptive processing, providing new opportunities for precision analgesia. Progress in photoswitches, photocaged ligands, wireless optoelectronic systems, and nanodelivery platforms has substantially improved the in vivo applicability of light-responsive therapeutics. These developments have transformed photopharmacology from a mechanistic research tool into a potential translational strategy for pain treatment. In this review, we discuss how photopharmacological approaches are reshaping the investigation of peripheral and central pain signaling, highlight emerging light-controlled analgesics, and outline future directions toward clinically translatable, nonaddictive, and personalized pain therapeutics.

Lysosome-targeted protein degradation (LTPD) represents a therapeutic strategy that degrades membrane and extracellular target proteins through the endolysosomal pathway. LTPD chimeras are molecular degraders that mediate LTPD, but their in vivo performance is limited by poor spatiotemporal control of degradation—existing chimeras have suboptimal pharmacokinetics, tissue selectivity, and endolysosomal trafficking. To overcome these hurdles associated with chimeras, LTPD platforms have emerged. LTPD platforms function as chimera-loaded systems for targeted delivery and controlled release of chimeras, or as platform-based degraders that mediate disease-targeted and on-demand degradation without chimeras. We discuss how LTPD platforms spatiotemporally control degradation and describe their therapeutic applications. In particular, we summarize the design principles of LTPD platforms to address the stringent requirements imposed by the LTPD process. These principles may contribute to the rational design of LTPD platforms.

Classic serotonergic psychedelics act primarily via 5-HT2A receptor agonism, yet their therapeutic effects and biological responses are heterogeneous. Biological sex remains an underexamined source of this variability because many clinical and preclinical studies have not been designed to test sex-by-treatment effects. Recent preclinical findings, together with more limited human evidence, suggest that sex and endocrine state can modulate serotonergic mechanisms relevant to psychedelic action, including 5-HT1A autoregulatory feedback, 5-HT2A signaling, serotonin clearance, neuroendocrine coupling, and neuroplastic cascades. This review synthesizes how sex- and state-sensitive serotonergic regulation may influence psychedelic signaling and outlines priorities for sex-informed translational research in preclinical and clinical settings.

Recent studies identify amyloidogenic human amylin, secreted by the pancreas, as a potential link between type-2 diabetes and Alzheimer’s disease. Evidence suggests that pathogenic amylin signaling impairs cerebral bioenergetics, promoting tau hyperphosphorylation and neurodegeneration. Selective targeting of circulating amyloidogenic amylin and its pathogenic signaling may enable biomarker development and disease-modifying therapies.

Pharmacological targeting of Signal Transducer and Activator of Transcription 3 (STAT3) in cancer has demonstrable antitumor efficacy. However, suitably potent, efficacious, and safe STAT3 inhibitors are scarce, and only a handful have entered clinical trials, limiting our knowledge of the extent of clinical benefit. Outcomes of recently completed trials in advanced cancers range from improved overall survival and complete responses in a cohort of patients with phosphotyrosine STAT3 positivity to partial responses and progressive disease in unselected patients. Advancements in oligonucleotide technologies and the integration of E3 ligase-specific proteolysis-targeting chimeras and molecular glue protein degrader strategies are accelerating the transition of STAT3 inhibitors into clinical testing. This review examines recent STAT3-targeted modalities and their preclinical and clinical activities. It concludes by underscoring the value of biomarker-informed approaches to optimize patient outcomes, combination therapies to improve clinical benefits, and artificial intelligence/machine learning tools to accelerate development.

The clinical translation of stimulator of interferon genes (STING)agonist-based cancer immunotherapy is limited by uncontrolled and sustained STING activation, which leads to immune exhaustion and systemic toxicity. In this forum, we critically analyze recent advances, including stimuli-responsive, biomimetic, pulsatile, intracellular-triggered release, and synergistic systems that enable precise spatiotemporal STING activation, as well as associated gaps in clinical translation. Finally, we present futuristic perspectives on next-generation STING-based cancer immunotherapy strategies.

Per- and polyfluoroalkyl substances (PFAS) are persistent xenobiotics linked to neurodevelopmental, neurodegenerative, and neurological disorders. PFAS-induced gut microbiota remodelling may disrupt gut-brain signalling, thereby affecting brain functions and behaviour. Integrating microbiome endpoints (diversity, taxonomic shifts, and metabolic configuration) into PFAS research provides a framework to elucidate toxicodynamic mechanisms and to inform the development of targeted, mechanism-based therapeutic strategies.

Angiogenesis fuels cancer progression, yet its immunomodulatory role in neuroendocrine malignancies remains poorly understood. Recently, Wang et al. identified a blood–brain barrier-like vascular gate that mediates immune exclusion and immunotherapy resistance in small-cell lung cancer. Targeting this barrier with OSI-906 enhances CD8+ T-cell infiltration and immunotherapy efficacy.

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.

STRUCTURE: Elamipretide hydrochloride (formerly known as Bendavia, S-133, or MTP-131; marketed as FORZINITY) is an aromatic-cationic synthetic tetrapeptide and the first-in-class therapy for Barth syndrome (BTHS). The molecular formula is C32H49N9O5·3HCl, with a molecular weight of 749.2 g/mol. The chemical name is l-phenylalaninamide, d-arginyl-2,6-dimethyl-l-tyrosyl-l-lysyl-, hydrochloride (1:3). The peptide sequence, d-Arg-Dmt-Lys-Phe-NH2, contains the noncanonical amino acid Dmt [(S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid].

The complement system is essential for distinguishing self-tissue from foreign threats; however, complement activation on biomedical surfaces such as implants, transplants, or drug-delivery systems may lead to severe thromboinflammatory complications. Unlike systemic complement inhibitors, surface-targeted strategies remain scarce, despite their potential advantages regarding safety and efficacy. Recent years have seen the emergence of diverse surface-targeting approaches that impair different mechanisms underlying complement-mediated complications. These strategies, ranging from surface coatings to inhibitors targeting complement-tagged surfaces, are progressing from conceptual development to clinical application. In this review, we provide a comprehensive overview of complement-activation mechanisms on biomedical surfaces, highlight ongoing clinical investigations, and discuss a broad spectrum of emerging approaches to prevent adverse complement activation on biomedical interfaces.

STRUCTURE: Vepdegestrant is an orally bioavailable heterobifunctional proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader with the molecular formula C45H49N5O4 and a molecular weight of 723.90 g/mol. The molecule combines an ER-binding ligand derived from an aryl-tetralin/tetrahydronaphthalene scaffold, a linker, and a cereblon-binding glutarimide–phthalimide moiety. This modular architecture enables the simultaneous binding of ER alpha and cereblon, promoting the formation of a productive ternary complex that drives ubiquitination and proteasomal degradation of the receptor.

Molecular chaperones play a central role in kinase homeostasis by guiding the folding, maturation, and stability of kinase clients. Yet advances in kinase folding and post-translational modification have not been adequately integrated into a coherent chaperone-centered framework, limiting a unified understanding of kinase homeostasis, and constraining more systematic efforts to target the chaperone–kinase axis. Recent structural and mechanistic studies now support a model in which chaperone assemblies function as regulatory platforms that coordinate kinase maturation, modification, and fate control. This review integrates these advances into a chaperone-centered view of kinase homeostasis and discusses pharmacological strategies targeting the chaperone–kinase axis, including chaperone modulation, interface disruption, and bifunctional approaches.

Spinocerebellar ataxias (SCAs), rare neurodegenerative disorders characterized by progressive cerebellar degeneration, cause impaired balance and motor dysfunction. Although most cases are inherited, sporadic forms also occur, and effective disease-modifying therapies remain unavailable despite advances in understanding their genetic and molecular mechanisms. This unmet need is particularly significant because many SCAs are monogenic disorders caused by well-characterized mutations, making them promising candidates for gene- and RNA-based therapies. Recent advances in antisense oligonucleotides, RNA interference, vector engineering, and genome editing have increasingly enabled the alignment of therapeutic strategies with specific mutational architectures. Therefore, this review aims to examine how genetic subclassification informs platform selection, summarize recent advances in gene- and RNA-based therapeutics, and outline key translational barriers to clinical implementation in SCAs.

STRUCTURE: Orforglipron (LY3502970 and OWL833) is a highly functionalized polycyclic heterocycle with the molecular formula C48H48F2N10O5 (molecular weight: 883.0 g/mol). It features a conformationally constrained 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine core, substituted at C3 by a 1,3-disubstituted 1,3-dihydro-2H-imidazol-2-one linker with N3 connecting to a 4-fluoro-1-methyl-1H-indazole moiety, at C4 by a methyl group, and at N2 by a 4-fluoro-3,5-dimethylphenyl ring. The N5 position is further linked via a carbonyl group to the C2 of (4S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole, which is capped at N1 by 3-[(1S,2S)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one.

Animal venoms represent rich sources of pharmacologically active molecules, yet their translation into clinical therapeutics has historically progressed slowly. Recent advances in AI-driven venomics, cryo-electron microscopy, and computational peptide engineering are helping to overcome long-standing barriers in venom-based drug discovery and accelerate therapeutic translation.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel predominantly expressed in sensory neurons. Genetic associations of TRPA1 with human diseases, along with extensive experimental evidence, have fueled interest in targeting TRPA1 for the treatment of pain, itch, and respiratory disorders. TRPA1 responds to a remarkably broad spectrum of agonists, including electrophilic and nonelectrophilic natural products, endogenous metabolites, marketed drugs, and synthetic compounds. Numerous antagonists have been identified, several of which have advanced into clinical trials. Recent cryogenic electron microscopy and mutagenesis studies have revealed at least ten distinct ligand-binding sites and modulation mechanisms. In this review, we highlight recent advances in the versatile pharmacology of TRPA1 and its therapeutic development, shaped by both natural and rationally designed modulators.

Living cell therapy and nonliving drugs are both key approaches for treating solid tumors. Engineering living cells with nonliving drugs harnesses their complementary advantages to enhance therapeutic outcomes. However, inappropriate engineering methods or design strategies can compromise the synergy between cells and drugs. In this review, we provide a decision framework that matches engineering strategies to cell types and drug properties, yielding baseline-qualified engineered cells. To address barriers specific to solid tumors, we then discuss strategies for equipping cells with additional functions that enable deeper penetration, resistance to immunosuppression, and controlled release. We also discuss emerging strategies to increase their safety during clinical translation. This review aims to guide the rational design of next-generation engineered cell therapies to achieve improved clinical outcomes.

Cancer is increasingly conceptualized as a disease of distorted human development, where oncogenic events trigger developmental reprogramming by subverting physiological lineage programs. Conventional cancer models often fail to capture this early transition, as they primarily reflect end-stage tumors or nonhuman biology. Human pluripotent stem cells (hPSCs) circumvent these limitations by enabling the reconstruction of oncogenic events within precisely defined human developmental trajectories. In this review, we examine emerging principles of lineage bias and differentiation arrest revealed by hPSC-derived models across brain, retinal, and myeloid malignancies, as well as hereditary cancer predispositions. Crucially, we discuss how these models reveal therapeutic windows linked to defined developmental states to reverse lineage hijacking, translating developmental insights into pharmacological strategies for early cancer interception.

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.