Biology subjects

Lee, S.-H.

Publications and source records attributed to Lee, S.-H..

At least 19 recordsLinked to original sources

bioRxiv2026

Manta and devil ray genome assemblies uncover signatures of pelagic adaptation

Manta and devil rays (Mobulidae) are iconic marine megafauna highly adapted to life in the open ocean, with forward-facing mouths, enlarged pectoral fins and specialised filter-feeding apparatus. These innovations have enabled mobulids to occupy vast pelagic habitats, yet the genetic changes underlying them remain poorly understood. Here we use a combination of chromatin conformation capture, PacBio HiFi and Nanopore long-reads to generate highly contiguous annotated chromosome-level reference genomes for two mobulid species: the Atlantic pygmy devil ray (Mobula hypostoma) and the Atlantic manta ray (Mobula yarae). The assemblies span 3.5 and 4.0 Gb, with contig N50s of 23.3 and 7.3 Mb, respectively. We combine these into a Progressive Cactus whole genome alignment with benthic batoid outgroups to characterise the landscape of structural variation and identify candidate molecular regions associated with pelagic adaptation. This approach revealed that over 1.5 million structural rearrangements occurred along the ancestral mobulid lineage, with deletions encompassing three times more sequence compared to the benthic sister lineage. Genes affected by mobulid specific deletions were significantly enriched for neurogenesis pathways linked to craniofacial patterning, with several deletions overlapping the putative promoter sequences of craniofacial and roof of mouth development genes. Our findings highlight candidate developmental pathways through which ancestral deletions may have driven mobulid adaptations, while the high-quality genome resources provide a foundation for comparative and functional studies in Chondrichthyes.

evolutionary biology↗

bioRxiv2026

A unique intestinal epithelial cell that expresses canonical lymphoid genes

Enterocytes and intestinal secretory cells harbor innate immunity. However, certain transcriptional programs -even beyond rearranged T- and B-cell receptor genes- are considered the exclusive purview of adaptive immune cells, including abundant and diverse intestinal intra-epithelial lymphocytes (IELs). Here, we identify and characterize columnar intestinal secretory cells that co-express classic epithelial and lymphoid genes, including Ptprc, Cd3e, Cd8a, and Gzma/b but not T- or B-cell receptors. These previously unrecognized epithelium-derived lymphoid-like cells (EDLCs) differ from any known resident cell type, including IELs or tuft cells. Rare in healthy mouse and human intestines, their numbers increase upon IL-25 stimulation or IL-10 receptor deficiency in vivo and upon IL-13 stimulation in vitro. EDLC chromatin is uniquely accessible at thousands of cis-elements, including lymphoid and epithelial loci. These findings reveal a transcriptionally and epigenetically distinct intestinal epithelial derivative that expresses prominent lymphoid character.

cell biology↗

bioRxiv2026

Nuclear Cathepsin L Remodels the Replication Machinery to Create a Therapeutic Vulnerability in Ovarian Cancer

Abstract Therapeutic resistance in ovarian cancer is frequently driven by persistent replication stress, yet the molecular mechanisms that convert replication stress into a therapeutically exploitable vulnerability remain incompletely understood. Here, we identify drug-induced nuclear cathepsin L (nCTSL) as a previously unrecognized regulator of replication stress and DNA repair. Clofarabine (CLF) combined with the ATR inhibitor AZD6738, or the CHK1 inhibitor prexasertib promoted nuclear accumulation of CTSL, where it remodeled the replication machinery through degradation of CCNE1, MCM3, MCM6, and geminin, accompanied by loss of RAD51 and 53BP1 and increased {gamma}H2AX and phospho-RPA2. DNA fiber analysis demonstrated marked inhibition of replication fork progression following CLF-based combinations, whereas CTSL depletion accelerated fork progression and abolished therapy-induced replication stress. Reconstitution with the nuclear M1F CTSL isoform restored replication restraint, confirming a direct role for nuclear CTSL in regulating replication dynamics. GFP-based DNA repair reporter assays further revealed that CLF-based combinations suppress DNA repair competence in a CTSL-dependent manner, indicating that nuclear CTSL couples replication stress amplification with functional inhibition of repair pathways. Functionally, CLF-based combinations selectively targeted transformed fallopian tube secretory epithelial cells while sparing non-transformed counterparts, demonstrated broad activity in patient-derived ovarian cancer ascites spheroids, and significantly inhibited tumor growth and prolonged survival in vivo. Collectively, our findings identify nuclear CTSL as a mechanistic driver of replication stress that remodels the replication machinery, impairs DNA repair, and creates a therapeutically exploitable vulnerability in ovarian cancer. We propose that nuclear CTSL promotes a transition from replication competence to replication catastrophe, thereby establishing a conceptual framework for biomarker-guided therapeutic strategies targeting CTSL-dependent replication stress.

cancer biology↗

bioRxiv2026

A genome-wide CRISPR activation map of surface protein expression in human CD4 T cells

Surface proteins define T cell identity and function, but the abundance of each protein is not determined by transcription alone. Existing genome-wide CRISPR screens in primary human T cells either profile the transcriptome or isolate cells based on a single functional or protein phenotype. Here we present SCITO-Perturb-seq, a novel platform that couples combinatorial-indexed single-cell cytometry sequencing with pooled CRISPR activation (CRISPRa) to map the causal regulation of 201 surface proteins across 3.6 million human CD4 T cells. We find that 16% of activated genes significantly alter the expression of at least one surface protein. By applying semi-nonnegative matrix factorization to the perturbation effect matrix, we identified five modules corresponding to known CD4 T cell states. Notably, these modules group surface proteins by their shared response to perturbation, revealing coordinated regulation of proteins that are not co-expressed in unperturbed cells. SCITO-Perturb-seq represents the first genome-wide CRISPRa screen paired with direct, high-dimensional surface protein profiling, providing a comprehensive regulatory map of the CD4 T cell surface proteome.

genomics↗

bioRxiv2026

Relational Structure Constrains Individual Value Estimates in Visual Working Memory

Reflecting how we organize visual experience in everyday memory, visual working memory is increasingly understood as a system in which individual item representations are organized within structures rather than maintained in isolation. Among these, relational structure may be especially consequential because, by specifying how one item value lies relative to another within a feature space, it could allow information about one remembered value to constrain which values are plausible for the other. Yet demonstrating such constraint is challenging because item-specific mnemonic evidence and relational evidence ordinarily support essentially the same estimate. We broke this equivalence with biased post-encoding feedback for one item, making item-specific and relation-based predictions for the other diverge. Across three experiments, participants remembered two sequentially presented orientations, with feedback for one shifted slightly clockwise or counterclockwise from its actual value. Participants incorporated this bias into memory for the feedback-provided orientation; critically, it also appeared in reports of the other orientation, which received no feedback, in the direction predicted by the signed angular offset linking the two remembered values. This feedback transfer weakened with increasing angular separation but occurred in both directions between the first and second orientations. These findings show that relational structure directly constrains individual value estimates in visual working memory, even for items encountered separately. By dissociating normally coincident item-specific and relation-based predictions, our approach reveals an otherwise hidden relational contribution. A probabilistic account explains these findings through joint inference from uncertain item-specific and relational evidence, with their relative uncertainties governing transfer strength.

neuroscience↗

bioRxiv2026

ProteinSketch translates spatial intuition into protein design with bimanual interaction in VR

Generative AI-based protein design can create diverse structures for desired functions but offers human designers limited control over three-dimensional architectures. We developed ProteinSketch, a bimanual virtual reality platform in which immersive backbone sketches and volumetric envelopes are directly created and translated into constraints for diffusion-based protein generation. RFdiffusion-based real-time refinement enabled interactive exploration and construction of user-specified protein topologies. Volumetric conditioning of sketched envelopes enabled high-fidelity control of anisometric geometries, confirmed by cryo-electron microscopy. These user-defined volumetric constraints enabled functional-binder design and extension of pre-existing minibinders to surfaces otherwise difficult to access within complex molecular environments using conventional design approaches. This collaborative human-AI framework integrates human spatial reasoning with generative AI for spatially directed, shape-controlled design of protein structure and function. One-sentence summaryImmersive ProteinSketch embeds human spatial reasoning in AI-guided design of protein topology, shape, and function.

bioengineering↗

bioRxiv2026

Cryptococcus neoformans rewires the conserved Wee1-CDK checkpoint through two divergent kinases required for replication-stress tolerance and virulence

Cell-cycle checkpoints couple cell division to environmental and intracellular stress. Here, we show that the human fungal pathogen Cryptococcus neoformans possesses two divergent Wee1-family kinases, CnSwe1 and CnSwe102, that retain conserved CDK-inhibitory activity but function differently from their counterparts in the canonical Saccharomyces cerevisiae morphogenesis checkpoint. The swe1{Delta} and swe102{Delta} mutants displayed distinct stress-response defects, and genetic analyses suggested a dosage-sensitive genetic interaction between SWE1 and SWE102. Although both proteins promoted Cdc28 tyrosine phosphorylation and elongated-cell morphology when expressed in S. cerevisiae, neither localized to the mother-bud neck in C. neoformans. Altered SWE1 dosage in the absence of SWE102 increased sensitivity to replicative and DNA-damaging stresses and perturbed cell-cycle progression under genotoxic conditions. Importantly, loss of SWE1 nearly abolished virulence in a murine infection model, and SWE102 also contributed to pathogenicity. Together, these findings indicate that the conserved Wee1-CDK module acts in C. neoformans as a dosage-sensitive checkpoint that promotes stress adaptation and fungal virulence.

microbiology↗

bioRxiv2026

NGFR/Ngfr-marked basal duct progenitors drive ductal--acinar regeneration in injured salivary glands

Severe salivary gland injury can cause chronic xerostomia and persistent secretory dysfunction, yet the epithelial populations that support repair remain poorly defined. Here, we identify NGFR/Ngfr as a conserved surface marker for isolating organoid-forming epithelial stem/progenitor cells from human and mouse salivary glands and show that mouse Ngfr-lineage cells contribute to ductal-acinar regeneration after injury. Single-cell transcriptomic analysis of human salivary gland tissue identified a restricted NGFR-expressing basal duct epithelial subpopulation with progenitor-like features and early positions along inferred epithelial differentiation trajectories. Functionally, NGFR-expressing cells showed enhanced primary and secondary organoid-forming capacity, and NGFR-enriched human organoids engrafted after transplantation into injured salivary glands of immunodeficient mice. In mouse salivary glands, isolated Ngfr-expressing cells showed enriched organoid-forming activity, and Ngfr expression localized to injury-associated ductal regions after duct ligation and local inflammatory injury. Ngfr-CreERT2 lineage tracing further showed that Ngfr-lineage cells contribute to ductal and acinar compartments during post-injury regeneration. Together, these findings establish NGFR/Ngfr as a conserved surface marker for prospectively isolating basal duct epithelial stem/progenitor populations with organoid-forming activity and injury-responsive ductal-acinar regenerative potential.

cell biology↗

bioRxiv2026

Engineering a Matrix-Preserving Vascular dECM Platform with Tunable Stiffness for In Vitro Vascular Remodeling

Pathologic arterial stiffening is a hallmark of vascular disease that contributes to maladaptive vascular remodeling and neointimal hyperplasia through vascular smooth muscle cell (VSMC) phenotypic switching. Yet, because vascular disease progression is governed by both biomechanical and extracellular matrix (ECM) alterations, existing in vitro models often fail to recapitulate the full complexity of the diseased vascular microenvironment. Here, we developed a bioactive decellularized extracellular matrix (dECM) and methacrylated hyaluronic acid (MeHA) composite scaffold platform with tunable stiffness that preserves native vascular ECM components while enabling controlled investigation of stiffness-dependent cell behavior. Proteomic analyses confirmed retention of key vascular matrisome components, including collagens and glycoproteins, following decellularization. Electrospun vascular dECM scaffolds maintained an aligned fibrous architecture and spanned stiffness ranges representative of healthy and pathologically stiffened arterial microenvironments. Within this matrix-preserving platform, human VSMCs cultured on stiff dECM scaffolds exhibited increased spreading, altered morphology, enhanced nuclear localization of YAP and survivin, and broad transcriptional changes consistent with a shift toward a proliferative, matrix-remodeling VSMC phenotype. Together, this bioactive, matrix-preserving platform enables mechanobiologically relevant modeling of stiffness-driven vascular remodeling and indicates YAP and survivin as candidate regulators of maladaptive VSMC mechanotransduction.

bioengineering↗

bioRxiv2026

Systematic Profiling of Essential Fungal Transcription Factors Uncovers Ezt1 as a Central Pathobiological and Morphogenic Regulator in Cryptococcus neoformans

Cryptococcus neoformans is a global fungal pathogen that causes fatal cryptococcosis, and the limitations of current antifungals underscore the urgent need for new therapeutics. Here we systematically investigate essential transcriptional regulators in C. neoformans as potential antifungal targets, developing experimental pipelines that assess growth requirement, essentiality and function through conditional gene expression, constitutive overexpression, and meiotic spore analysis. We identify one quasi-essential (growth-required but non-essential) transcription factor, Fhl1, and 13 essential transcriptional regulators, three of which are transcription factors (Ezt1, Ezt2 and Cbf1) highly divergent from counterparts in other eukaryotes. Notably, Ezt1 modulates the expression of more than 1,200 genes, controlling growth, antifungal drug and stress responses, sexual development and virulence. Our findings define the essential transcriptional regulator landscape of C. neoformans and provide a framework for prioritising divergent essential regulators, particularly Ezt1, for antifungal target discovery.

microbiology↗

bioRxiv2026

Early Visual Cortex Represents Sensory and Mnemonic Orientations in Separate Subspaces with Preserved Geometry

How early visual cortex (EVC) represents working memory (WM) content while continuing to process incoming sensory input remains unclear. Using fMRI with prolonged delays to isolate mnemonic activity, together with analyses of cross-decoding, low-dimensional subspace structure, and representational geometry, we examined the relationship between sensory and mnemonic orientation representations in human EVC. Cross-decoding generalized poorly between sensory and mnemonic epochs, but this did not imply unrelated codes. Rather, the two occupied separable low-dimensional subspaces while preserving representational geometry across epochs. During discrimination and estimation, sensory- and mnemonic-trained decoders yielded dissociable readouts of concurrent sensory and mnemonic information from the same EVC measurements. Mnemonic coding showed little dependence on the retinotopic radial bias that characterized sensory coding, and trial-by-trial variability in mnemonic representation predicted both discrimination choices and estimation reports. Our findings support a population-level account in which mnemonic information in EVC is re-expressed in a separable but geometrically preserved format.

neuroscience↗

bioRxiv2026

Epigenetic control of S100A8/A9-driven monocytic inflammation licenses anti-leukemic functionality of immature NK cells during hematopoietic stem cell differentiation.

Inflammation is a key driver of hematopoietic dysfunction in myeloid malignancies, but its role in the context of hypomethylating therapy remains incompletely understood. Although 5-Azacytidine is used posttransplant in high-risk myelodysplastic syndrome (MDS), only 50% of patients show a clinical response. We provide evidence that inherent inflammatory properties of healthy donor CD34+ stem cells exist that are likely to contribute to the "response" seen in MDS patients. These are linked to epigenetic priming of the myeloid niche, resulting in S100A8/A9-driven inflammatory program that promotes functionality of immature NK cells. Using in vitro differentiation systems, multi-omic profiling, and a S100A9-/- mouse model, we find that 5-AzaC modulates inflammatory transcriptional programs through epigenetic rewiring of upstream regulatory elements. Loss of S100A9 disrupts myeloid differentiation, impairs NK cell maturation, and alters key developmental regulators including CEBPB, JUN, and NFIL3. In vivo, 5-AzaC restores these defects and primes NK cells in a time- and context-dependent manner. Re-analysis of the published Australian MDS/CMML cohort shows that "responders" display increased S100A8/A9 expression together with enhanced IFN-{gamma}, IL6-JAK-STAT3, and TNF signaling. These findings suggest that inflammatory myeloid programs may serve as predictive biomarkers and therapeutic targets to enhance NK cell-mediated graft-versus-leukemia activity posttransplant. SummaryO_LIWe provide compelling evidence that inherent properties of healthy donor CD34+ hematopoietic stem cells (SCs) exist that are likely to contribute to the "response" seen upon pre-emptive posttransplant 5-AzaC therapy of patients with high-risk myelodysplastic syndrome (MDS). C_LIO_LIThese properties are linked to a distinct form of epigenetic plasticity at upstream-located transcription factor (TF) binding sites. This may indirectly contribute to acute S100A8/A9-driven inflammation, which is demonstrable in distinct monocyte subsets and, importantly, also in NK cells thereby determining the characteristics of inflammatory monocyte-NK cell crosstalk. C_LIO_LIMice with a targeted deletion of S100A9 fail to upregulate CEBPB / JUN and NFIL3 which results in impaired myeloid priming and dysfunctional NK cell maturation, respectively. C_LIO_LIRe-analysis of the Australian MDS/CMML cohort confirms that MDS patients that "respond" to 5-AzaC exhibit activated IFN-{gamma}, IL6-JAK-STAT3, and TNF-signaling pathways in the context of upregulated S100A8/A9 after six months of treatment. C_LIO_LIOur study indicates that screening of healthy donors SCs for specific inflammatory markers in early developing monocytes could be used as a marker to predict which donor will have the potential of generating a S100A8/A9-driven inflammatory response. This may help identify patients with MDS as well as AML who are likely to benefit from low-dose, short-term 5-AzaC therapy as early as day 7 after transplantation, potentially resulting in increased graft-versus-leukemia (GvL) activity. C_LI

immunology↗

bioRxiv2026

CDS-BART: A BART-Based Foundation Model for mRNA Sequence Analysis

Summary: Recent advancements in artificial intelligence (AI) have led to the development of foundation models that interpret mRNA as a language. Notable examples include CodonBERT, hydraRNA, EVO2, and Helix-mRNA. These models demonstrate significant potential as powerful tools for mRNA research. However, to best of our knowledge, there is currently no publicly available AI model that is both easy to use and capable of analyzing mRNA sequences up to about 4kb, a length scale typical of many therapeutic mRNAs, including those encapsulated within lipid nanoparticls (LNPs). Thus, we propose CDS-BART, a user-friendly, open-source tool that integrates SentencePiece sub-word tokenization with the denoising sequence-to-sequence training of Bidirectional and Auto-Regressive Transformers (BART). CDS-BART was pre-trained on mRNA data from nine taxonomic groups provided by the NCBI RefSeq database. This comprehensive pre-training, coupled with BARTs denoising capability, ensures effective learning of codon usage, mRNA structure, evolution, and regulation. Thus, CDS-BART can ultimately deliver robust performance across a wide range of mRNA prediction tasks. Availability and ImplementationCDS-BART is released under the MIT License. Latest code is available via Github at https://github.com/mogam-ai/CDS-BART.

bioinformatics↗

bioRxiv2026

Deep Learning-Driven Discovery of Mitochondrial Factors Modulating Influenza A Virus Infection

Influenza A virus exploits host cellular machinery across subcellular compartments, yet the organelle-level changes that distinguish infected from uninfected cells and the molecular players driving them remain poorly defined. Here, we combine organelle image-based deep learning with proximity labeling chemoproteomics to address this gap. A convolutional neural network identified mitochondrial morphology as the strongest single-cell predictor of infection status (precision = 84.9%). Proximity labeling profiling of mitochondrial matrix proteome revealed 99 proteins with significantly altered upon infection, of which five (CH60, ETHE1, LONM, MPPB, and SQOR) were validated as host restriction factors whose depletion elevated interferon-{beta} expression, enhanced viral RNA accumulation, or increased progeny virus production. Notably, two of these factors, ETHE1 and SQOR, operate within the mitochondrial hydrogen sulfide oxidation pathway, and pharmacological scavenging of H2S by hydroxocobalamin dose-dependently reversed their knockdown phenotypes, directly linking mitochondrial sulfide metabolism to antiviral defense against influenza.

microbiology↗

bioRxiv2026

Dynamic Mechanical Loading Reprograms Meniscus Cell-Derived Extracellular Vesicles to Enhance Their Regenerative Potency

The meniscus is a fibrocartilaginous tissue critical for knee stability and load distribution, but its poor healing capacity makes regeneration after injury a major clinical challenge. Extracellular vesicles (EVs) are emerging as promising cell-free therapeutics for tissue regeneration. However, their clinical translation remains limited by low yield and variable bioactivity. Here, we investigated how dynamic mechanical loading regulates the production, composition, and function of meniscus fibrochondrocyte-derived EVs (MFC-EVs). Using a custom bioreactor system, cells were subjected to physiologically relevant cyclic tensile loading. Mechanical stimulation significantly increased EV production and secretion, likely through the ESCRT-independent pathway, without altering vesicle size or tetraspanin expression. Functionally, "mechanically primed" EVs enhanced aggrecan expression in recipient mesenchymal stromal cells (MSCs), mirroring the loading-response phenotype of their source cells. Proteomic profiling identified 380 unique proteins across all EV groups, with loaded EVs enriched in extracellular matrix- and cytoskeleton-associated proteins, as well as pathways related to tissue morphogenesis, cell migration, and cartilage development. Together, these findings demonstrate that physiologic mechanical loading enhances both the yield and regenerative potency of MFC-EVs by enriching their cargo with matrix- and development-associated proteins, providing a scalable and biologically inspired approach for engineering high-efficacy EV therapeutics for meniscus repair and musculoskeletal regeneration.

bioengineering↗

bioRxiv2026

Pharmacological intervention targeting neuroimmune axis in the aging hypothalamus prevents age-associated physiological decline

Systemic physiological aging is largely driven by disrupted metabolic homeostasis, yet the central mechanisms of this metabolic dysfunction remain poorly defined. Here, we identify the hypothalamus as a critical hub driving systemic aging through neuroimmune-mediated mechanisms. Single-cell transcriptomic and immunohistochemical analyses revealed that aged hypothalami exhibit significant infiltration of CD8 T lymphocytes, beginning in middle age, with signatures of activation and tissue residency. These T cells intimately interact with tanycytes and microglia, promoting neuroinflammation and progressive tanycyte loss, a defining hallmark of hypothalamic aging. T cell receptor profiling revealed a substantial presence of invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, likely activated through cytokine-driven, antigen-independent mechanisms. In aged hypothalamus, microglia secrete chemokines CCL3 and CCL4, whose ectopic expression in young mice was sufficient to trigger persistent hypothalamic T cell infiltration and accelerated systemic aging. Circulating oxidized LDLs (OxLDLs) were identified as upstream inducers of this chemokine response. Notably, pharmacological blockade of the CCL3/4-CCR5 axis with Maraviroc and Cenicriviroc prevented T cell recruitment and ameliorated metabolic and physiological impairments. Given the clinical safety of CCR5 antagonists and individuals lacking functional CCR5 remain generally healthy throughout life, our findings highlight midlife CCL3/4-CCR5 inhibition as a translatable therapeutic target for delaying age-related decline and promoting healthspan.

neuroscience↗

bioRxiv2025

Oncogenic RAS activity is linked to immune priming and adenosine-driven immune evasion in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is a leading cause of cancer death worldwide, with RAS signalling as a key oncogenic driver. Although KRAS mutations have been linked to immune evasion in preclinical models, the relationship between RAS activity and tumour immunity or response to immunotherapy in patients remains unclear. Here, we applied our previously validated RAS84 transcriptional signature to stratify LUAD patient cohorts and dissect the immune landscape associated with RAS signalling. We report that tumours with elevated RAS activity exhibited features of immune priming, including increased immune infiltration, interferon response, and immune checkpoint gene expression, and showed improved progression-free survival in an independent cohort of patients treated with anti-PD-1. Yet, in both LUAD tumours and cell lines, RAS activity also correlated with elevated immunosuppressive interstitial adenosine mediated by transcriptional regulation of several components of the adenosinergic pathway. In orthotopic pre-clinical models of high-RAS activity lung tumours, blocking adenosine signalling delayed tumour growth and improved response to anti-PD-1 and KRAS inhibition, with a significant effect on innate immunity. This study reveals a dual role for RAS signalling in tumour progression, fostering a pro-immunogenic environment whilst simultaneously dampening anti-tumoural immunity via mechanisms including extracellular adenosine accumulation. Stratifying patients based on RAS transcriptional activity, rather than genetic alterations alone, could inform immunotherapy strategies and improve clinical outcomes.

cancer biology↗

bioRxiv2025

CRISPR-Induced NUT Suppression Promotes Differentiation and Enhances Trop2-Targeted Immunocytokine Response in NUT Carcinoma

NUT carcinoma (NC) is an aggressive malignancy driven by NUTM1 gene rearrangements with limited therapeutic options. Here, we show that direct suppression of NUTM1 using CRISPR/Cas9 induces squamous-like differentiation and upregulates TROP2 expression in NC cells. Building on this finding, we developed a TROP2-interferon beta (IFN-{beta}) mutein immunocytokine that selectively targets TROP2-expressing tumors. Combined NUTM1 suppression and TROP2-targeted immunotherapy synergistically enhanced cytotoxic and immune-mediated responses in vitro. Transcriptomic and spatial analyses of NC patient tumors revealed that differentiation status correlates with TROP2 expression, upregulated immune pathways, and favorable clinical outcomes. Our results suggest that overcoming differentiation blockade not only alters tumor phenotype but also creates a more immune-permissive microenvironment. These findings highlight the therapeutic potential of sequential tumor reprogramming followed by targeted immunotherapy in treating NC and propose a broader strategy for overcoming differentiation blockade in fusion-driven cancers.

cancer biology↗