Biology subjects

Ye, Y.

Publications and source records attributed to Ye, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Porcine extended pluripotent stem cell-derived somite-like mesoderm cells with Dox-driven PAX7 are robust seed cell resource for facilitating production of cultured meat

Cultured meat technology, with its significant advantages of shortening meat production cycles, reducing natural resource consumption, minimizing the risk of zoonotic disease transmission, and enabling precise control over nutritional composition and texture, offers a novel alternative source for human meat consumption. One of the major challenges to produce cultured meat in large scale is how to establish high.quality seed cells, which should have long term proliferative capacities and are able to differentiate into muscles efficienuy with simple procedures. Here, we first established an engineered porcine expanded potential stem cells (Tet-On-PAX7 EPSCs) containing Tet-On regulated PAX7 gene. Then the Tet-On-PAX7 EPSCs were induced to somite-liKe mesodermal cells. These somite-liKe mesodermal cells can be expanded over 1025-fold even after 40 passages in-vitro culture while retaining strong myogenic potential. The somite-like mesodermal cells treated with DOX for one day would differentiate into muscle stem cells (Muses), and the later were able to differentiate into muscles with an efficiency of up to 90% within just 7 days in 11-FSDeDa without Dox. Moreover, when somite-liKe mesodermal cells were seeded on patterned scaffolds, microcarrier scaffolds, or cultured in anchorage-independent suspension, they maintained high efficiency in muscle differentiation, confirming their potential to be used as seed cells for scaled cultured meat production.

developmental biology↗

bioRxiv2026

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines. ADT-030 is orally bioavailable and effectively suppresses tumor growth across multiple syngeneic mouse models. Notably, its efficacy is diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunostimulatory properties of ADT-030 are further supported by its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation, its reliance on Batf3-expressing DCs to elicit antitumor CD8+ T cell response, and its synergy with anti-PD-1 therapy. Comprehensive immune profiling in the 4T1 breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces myeloid-derived suppressor cells (MDSCs) while normalizing the immune landscape within the tumor. Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity.

immunology↗

bioRxiv2026

Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota-Butyrate-Vagus Nerve-Brain Axis

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical-translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve-dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid-producing bacteria, including Akkermansia muciniphila, Prevotella, Alistipes, and Odoribacter. Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota-butyrate-vagal pathway essential for the therapeutic effects of VNS, highlighting the gut-brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/707138v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@8243e6org.highwire.dtl.DTLVardef@37f0e6org.highwire.dtl.DTLVardef@a8b321org.highwire.dtl.DTLVardef@1887342_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIVagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. C_LIO_LIVNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila, in both humans and mice. C_LIO_LITransplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. C_LIO_LIAkkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway. C_LI

neuroscience↗

bioRxiv2026

Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis

Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimers disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5xFAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2, a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-{beta} burden, restore synaptic plasticity, and improve cognitive function in 5xFAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.

neuroscience↗

bioRxiv2026

ATLAS: Population-Level Disease Locus Discovery via Differential Attention in Genomic Language Models

Identifying disease-associated genetic variants remains a key challenge in genomics, especially in small cohorts or for rare and complex mutation types where genome-wide association studies (GWAS) often fall short. We introduce ATLAS, a population-level framework that leverages attention signals from pretrained genomic language models (gLMs) to detect disease-associated genes and loci directly from raw sequences--without requiring explicit variant calls or supervised training. ATLAS first performs gene-level differential attention analysis to prioritize candidate genes, followed by base-level analysis to localize disease-associated regions at single-haplotype resolution. We validate ATLAS on synthetic and {beta}-thalassemia datasets, demonstrating robust performance across diverse allele frequencies (down to 10%), cohort sizes (below 200 individuals per group), and genomic scales. Compared to GWAS, ATLAS achieves higher recall of known loci and captures haplotype-specific signals missed by traditional methods. Cross-model benchmarking further shows that precise localization depends on both model size and pretraining on diverse human genomes. In summary, ATLAS offers a scalable, sequence-native alternative to traditional statistical genetics.

genetics↗

bioRxiv2026

RSAD2/VIPERIN and CMPK2 Coordinate an Immunometabolic Response to Epstein-Barr Virus

Epstein-Barr Virus (EBV) infection and reactivation in B-lymphocytes is tightly regulated by host antiviral response genes. In the present study, we identify interferon stimulated genes RSAD2 (radical S-adenosyl methionine domain-containing 2) and CMPK2 (Cytidine/Uridine Monophosphate Kinase 2) as key modulators of EBV expression and cellular response during EBV infection and reactivation. EBV primary infection and reactivation lead to a coordinated up-regulation of RSAD2 and CMPK2. Depletion of RSAD2 reduced cell viability and limited EBV reactivation, while depletion of CMPK2 led to reactivation of EBV lytic gene expression during latency. Transcriptomic analysis revealed that RSAD2 and CMPK2 have overlapping functions in regulating IFN-signaling pathways, as well as oxidative phosphorylation, protein translation, and unfolded protein response during reactivation. Despite distinct subcellular localizations, RSAD2 at the Endoplasmic Reticulum (ER), and CMPK2 in mitochondria, both genes converge on shared immunometabolic pathways, including control of Gasdermin D (GSDMD) associated pyroptosis and ATF-4 associated unfolded protein response (UPR). EBV reactivation induced formation of antiviral ribonucleotide ddhCTP during lytic EBV reactivation which was strictly dependent on RSAD2. Knockdown of RSAD2 and CMPK2 had significant effects on global metabolites consistent with a remodeling of glycolysis, fatty acid biosynthesis and degradation of superoxides. These observations demonstrate that RSAD2-CMPK2 function in a coordinated ER-mitochondria stress-Interferon signaling axis that shapes EBV reactivation and host immune control, including a novel layer of immunometabolic regulation modulating viral latency and reactivation. Authors SummaryUnderstanding how Epstein-Barr virus (EBV) regulates host factors to control infection, latency and reactivation is critical for developing targeted therapies against EBV-associated diseases. This study identifies Interferon Stimulated Genes RSAD2 (Viperin) and CMPK2 as key regulators of EBV reactivation and host interferon responses in B-cells. Despite distinct organelle localizations, both genes converge on a shared immunometabolic pathways, revealing a coordinated ER-mitochondria axis that shapes viral expression and immune signaling. These findings provide new insights into the roles of host antiviral effectors and uncover potential targets for modulating EBV activity in inflammatory and oncogenic contexts.

microbiology↗

bioRxiv2026

Indomethacin exerts both cyclooxygenase inhibition-dependent and independent mechanisms to enhance chemo-immunotherapy in mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily act by inhibiting cyclooxygenases (COX1 and COX2), thereby reducing production of the proinflammatory mediator prostaglandin E2 (PGE2). Because PGE2 is a critical driver of cancer progression and tumor immune evasion, this has motivated interest in combining NSAIDs with chemotherapy or immunotherapy for cancer treatment. However, since COX and PGE2 levels vary across tumor types, it remains unclear whether tumor PGE2 abundance solely dictates tumor response to NSAID-based therapies. Here, we investigated the therapeutic potential of indomethacin (Indo), a prototypical NSAID, in combination with cyclophosphamide (CTX), a widely used chemotherapeutic agent with immunostimulatory properties. Metronomic administration of Indo significantly enhanced the antitumor efficacy of CTX in multiple murine tumor models exhibiting variable COX2 and PGE2 levels, including CT26, MC38, 4T1 and A20. The antitumor effects of CTX+Indo required CD8 T cells and T-cell trafficking from tumor-draining lymph nodes and were further potentiated by anti-PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that responsive CT26 tumors exhibited a reprogrammed tumor immune microenvironment (TIME), marked by increased effector CD8 T-cell infiltration, reduced immunosuppressive myeloid populations, and enhanced interferon signaling in tumor cells. Importantly, Indo retained therapeutic benefit following CTX even in tumors incapable of producing PGE2, demonstrating a critical contribution of COX-independent mechanisms, particularly inhibition of tumor-intrinsic oncogenic RAS signaling, to the enhanced efficacy of the CTX+Indo combination. Collectively, our results provide strong preclinical rationale for leveraging the COX/PGE2 and RAS dual inhibitory capacities of NSAIDs to enhance the efficacy of chemotherapy and immunotherapy.

immunology↗

bioRxiv2025

Multimodal AI for Single cfDNA Profiling and Cancer Screening

Cell-free DNA (cfDNA) serves as a non-invasive biomarker for cancer detection, but conventional methods face challenges due to the ultra-low abundance of tumor-derived cfDNA (ctDNA) among normal cfDNA. Though nucleosome-bound cfDNA harbors rich epigenomic features that could enable ctDNA identification by single-molecule multi-omics cross-validation, this remains unexplored due to methodological limits. Here, we developed a cfDNA sequencing approach integrating methylation, fragmentomics, and histone modifications at the single-molecule level; together with gene semantics and epigenomic annotations, these modalities were vectorized and fused to represent each cfDNA molecule. We trained a Transformer-based model (cfAI) to profile and evaluate ctDNA likelihood at molecule, gene, and sample levels. cfAI achieved [~]10-fold enrichment of cancer-derived signals over noise and reached 72.6% sensitivity at 93.1% specificity for multi-cancer detection. Our study establishes an innovative framework that overcomes the inherent signal-to-noise limitations of conventional assays and reveals biological features at molecular resolution for cancer detection.

bioinformatics↗

bioRxiv2025

Nuclear export governs TDP-43 phase transitions and cytoplasmic aggregation

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like, nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanism(s) that governs the liquid-to-solid phase transition of TDP-43 is poorly defined. Here we combined chemical and genome-wide genetic screenings to identify cellular factors that modulate the phase behavior of an RNA-binding defective TDP-43 mutant. Our screens uncovered multiple cellular processes including RNA splicing, protein translation, proteostasis imbalance and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.

cell biology↗

bioRxiv2025

Cross-chemical and cross-species toxicity prediction: benchmarkingand a novel 3D-structure-based deep learning model

Prediction of a compounds toxicity is a key step toward realizing animal-free testing of chemical compounds. Recent advances have yielded significant progress in computational toxicity prediction, including machine learning methods that utilize chemical fingerprints and deep learning-based latent representations. However, challenges remain, primarily due to the lack of clean training datasets and the inconsistent model performance. To address these challenges, we curated a comprehensive dataset of aquatic toxicity from seven data sources, which contains 50,603 records for 5,889 compounds across 2,285 different species, much larger than similar datasets used in previous studies. We also developed tox-learn, a Python library featuring tools for automated dataset cleaning, machine learning methods and performance evaluation. The library places special emphasis on avoiding overestimation of prediction accuracy caused by improper train-test data splitting. Based on this toolbox, we benchmarked various predictive models using different train-test splitting strategies on the curated dataset. Our results showed that the choice of machine learning method, molecular fingerprint, and train-test splitting strategy all significantly affect performance. We demonstrated that incorporating species information generally improved predictions, although the degree of improvement depended on how this information was represented. In addition, we developed a new 3D structure-based deep-learning model, 3DMol-Tox, which achieves regression accuracy comparable to the best 2D-structure based model (GPBoost) while exhibiting consistently higher within-one-bin (W1B) classification accuracy. Finally, we analyzed the impact of different train-test splitting strategies and provide recommendations based on our benchmarking, such as using structure-aware splitting to mitigate information leakage, a common issue that inflates reported model performance.

bioinformatics↗

bioRxiv2025

A human forebrain organoid model phenocopies dysregulated RNA and protein homeostasis in ALS/FTD-associated TDP-43 proteinopathies

TAR DNA-binding protein 43 (TDP-43) proteinopathy is a defining pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet the downstream molecular events linking TDP-43 dysfunction to neurodegeneration remain incompletely understood. Here, we model TDP-43 proteinopathy by introducing the ALS/FTD-associated TARDBP K181E mutation into human induced pluripotent stem cells and differentiating them into three-dimensional forebrain organoids. Organoids carrying the K181E mutation exhibit spontaneous TDP-43 hyperphosphorylation, cytoplasmic p-TDP43 accumulation, RNA dysregulation, pro-inflammatory signaling, and activation of apoptotic pathways without TDP-43 overexpression or external stress. Single-cell transcriptomics and enhanced crosslinking immunoprecipitation reveal that the K181E mutation alters TDP-43 RNA-binding specificity, causing widespread RNA mis-splicing including cryptic exon inclusion. Among affected targets, we identify cryptic exon inclusion in the transcription factor PRDM2. PRDM2 cryptic exon-derived peptide immunoreactivity was detected in ALS spinal motor neurons and associated with p-TDP-43 pathology. These findings identify PRDM2 mis-splicing as a candidate downstream event linking TDP-43 dysfunction relevant to ALS and FTD. One sentence summaryHuman brain organoids reveal how mutant TDP-43 disrupts RNA processing and causes neuronal stress.

neuroscience↗

bioRxiv2025

Derivation, Characterizations, and Applications of Rabbit Haploid Embryonic Stem Cells

Haploid embryonic stem cells (haESCs), which contain a single set of chromosomes, provide powerful systems for investigating gene function and creating gene-edited animal models. haESCs have been derived from several mammalian species including human, mouse and rats, yet not from rabbits. Here, we report the derivation of parthenogenetic haESCs of rabbit (rbPhESCs) using an optimized culture medium. These cells maintain a stable haploid karyotype during long-term culture and own pluripotency features comparable to diploid embryonic stem cells derived from rabbit fertilized embryos. By integrating gene trapping cassette into ROSA26 locus, rbPhESCs offer an ideal platform for high-throughput functional genomic screening, as shown in haESCs from other mammals. Consistent with their parthenogenetic origin, rbPhESCs durably preserve maternal-specific imprinting patterns even after extended culture in serum-containing conditions, providing a valuable platform for generating disease models deficient in maternally expressed imprinted genes. Therefore, our findings expand the repertoire of mammalian haESCs and establish rbPhESCs as a valuable platform for genetic studies and biotechnological applications in rabbits.

cell biology↗

bioRxiv2025

Mist4Cores: Reliable batch image stitching for dendrochronological cores

MIST4Cores automates the end-to-end process of image stitching for camera-based methods. This software allows reliable stitching with customizable user configuration and directory monitoring through overlap analysis and plugin-driven assembly. Each function in the software serves a distinct role in facilitating robust, reproducible, and user-friendly image stitching for scientific workflows. The combination of free open software tools for image acquisition, image stitching, and image analysis creates an open-source ecosystem to promote further research in the dendrochronological area.

ecology↗

bioRxiv2025

Identification and characterization of emNagⅡ, a novel β-1,2-N-acetylglucosaminidase from Elizabethkingia meningoseptica

N-Acetylglucosamine exists in various forms and linkage patterns within organisms, playing a crucial role in numerous vital biological processes. However, research focusing on {beta}-1,2-linked N-acetylglucosamine within complex biantennary N-glycans on the cell surface remain largely unexplored. Currently, there is a lack of efficient tools and methods capable of directly modifying terminal N-acetylglucosamine on living cells. In this study, we identified a novel {beta}-N-acetylhexosaminidase from Elizabethkingia meningoseptica, which demonstrated favorable enzymatic stability within a pH range of 5-8 and at temperatures from 4 {degrees}C to 37 {degrees}C. This enzyme specifically cleaves non-reducing terminal {beta}-1,2-N-acetylglucosamine, enabling direct removal of this modification from oligosaccharides and native glycoproteins. More importantly, we demonstrate for the first time that this enzyme successfully removes {beta}-1,2-linked N-acetylglucosamine on living cell surfaces. Given its microbial origin and potential utility in living cell glycan editing, we have named it emNagII or cell-surface glycan-editing N-acetylglucosaminidase (csgeNagII). Through sequence analysis and alanine scanning mutagenesis, we identified a predicted active pocket containing the catalytic residue pair Asp317-Glu318, with Asp317 being essential for enzymatic activity. In summary, our findings provide an effective and reliable method for the targeted removal of {beta}-1,2-N-acetylglucosamine on living cell surfaces, establishing a foundation for further functional studies and practical applications.

biophysics↗

bioRxiv2025

BandHiC: a memory-efficient and user-friendly Python package for organizing and analyzing Hi-C matrices down to sub-kilobase resolution

Recent advances in high-resolution Hi-C and Micro-C technologies have enabled finer-scale characterization of 3D genome architecture, but they also introduce substantial computational challenges, as the size of dense contact matrices scales quadratically with resolution, resulting in prohibitive memory demands. To address this, we developed BandHiC, a memory-efficient and user-friendly Python package for organizing and analyzing Hi-C matrices down to sub-kilobase resolution. BandHiC adopts a banded storage strategy that preserves only a configurable diagonal bandwidth of the dense contact matrix, reducing memory usage by up to 99% while maintaining fast random access and intuitive indexing operations. In addition, it provides flexible masking mechanisms to handle missing values, outliers, and unmappable regions, and supports efficient vectorized operations optimized with NumPy, thereby enabling scalable analysis of ultra-high-resolution Hi-C datasets.

bioinformatics↗

bioRxiv2025

LINE1 RNA dysregulation impairs chromatin accessibility in C9ORF72- and TDP-43-linked ALS/FTD

The long interspersed element-1 (LINE1) retrotransposon RNAs are abnormally elevated in various neurodegenerative disorders, but their pathogenic roles remain unclear. Here we investigated the mechanism of LINE1 RNA accumulation and its function in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with C9ORF72 repeat expansion and TDP-43 loss-of-function, the leading causes of familial and sporadic forms of these neurodegenerative diseases. We show that LINE1 RNA is dysregulated due to an impaired nuclear exosome targeting (NEXT) degradation pathway. Its elevation epigenetically increases chromatin accessibility, enhancing global transcription via a retrotransposon-independent mechanism. Reducing LINE1 RNA mitigates chromosomal abnormalities and improves the survival of disease-relevant neurons. These findings uncover an essential noncoding RNA function and regulatory mechanism of LINE1 in neurons, providing insights into disease pathogenesis and highlighting potential therapeutic targets for neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Disrupted Regional Dynamics of Structure-Function Connectivity Coupling in Euthymic Bipolar Disorder

BackgroundBipolar disorder (BD) is characterized by persistent disturbances in emotional regulation and cognitive function, even during euthymia, yet its neural mechanisms remain unclear. Given evidence of structural and dynamic functional connectivity (dFC) abnormalities in BD, investigating dynamic structure-function connectivity coupling (SC-FC coupling) may provide insights into the pathophysiology of the disorder. MethodsDiffusion tensor imaging and resting-state fMRI data were collected from 61 euthymic BD-I patients and 54 healthy controls (HC). Structural connectivity was derived using probabilistic tractography, and dFC was estimated with a sliding-window approach. SC-FC coupling was quantified as the extent to which structural features predicted dFC using multivariate linear regression. Abnormal SC-FC coupling in BD was assessed at both the network and regional levels, relative to HC. Over time, SC-FC coupling was categorized into high- and low-coupling states, and dynamic state analyses of dwell time, occurrence rate, and transition probabilities were performed in the affected brain regions. ResultsNetwork-level analyses indicated that BD exhibits lower SC-FC coupling in subcortical regions compared with HC. Regional analyses revealed significantly reduced dynamic SC-FC coupling in two thalamic subregions (medial posterior and rostral temporal) and in the right primary somatosensory cortex in BD compared to HC. Dynamic analyses further demonstrated thalamic instability: BD showed shorter dwell times in high-coupling states, increased occurrence of low-coupling states, and more frequent high-to-low coupling transitions than HC. These abnormalities suggest that BD is characterized by disrupted structure-function integration and unstable thalamocortical dynamics. ConclusionOur findings reveal regional abnormalities in SC-FC coupling dynamics in BD, indicating persistent dysfunction of structure-function integration during euthymia. Dynamic coupling measures may provide preliminary insights into potential biomarkers for disease monitoring.

neuroscience↗

bioRxiv2025

Chemotherapy Induces an IL1β-dependent Neutrophil Recruitment that Promotes Chemoresistance in Metastatic Ovarian Cancer

High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis. How chemotherapy-induced remodeling of the tumor microenvironment modulates drug sensitivity remains unclear. In this study, we demonstrate that chemotherapy induced IL1{beta}-dependent neutrophil accumulation in tumors, driving chemoresistance in HGSC. Using patient samples, bulk transcriptomic profiling before and after chemotherapy revealed post-treatment upregulation of IL1B, and single-cell RNA sequencing identified myeloid cells as its principal source. In a chemoresistant murine metastatic ovarian cancer model, chemotherapy increased neutrophils and neutrophil extracellular traps (NETs) in omentum tumors; these increases were abrogated in IL1{beta}-deficient mice, with expansion of activated CD8+ T cells and tumor control. Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1{beta}-deficient mice. In vitro, IL1{beta} did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Additionally, the dominant IL1{beta} receptor (IL1R1) was predominantly expressed in tumor-associated fibroblasts in humans and mice. Consistently, IL1R1-deficient mice exhibited chemosensitivity with decreased neutrophil accumulation and increased IFN{gamma}TNFCD8 T cells. We also found that chemotherapy upregulated CXCL2 in patients and that ablating IL1{beta}-IL1R1 axis decreased CXCL2 expression in tumor-associated fibroblasts in mice. Finally, residual human HGSC tumor after chemotherapy showed increased neutrophils and a trend toward more NETs. Collectively, these findings illuminate a paradoxical, cancer cell-extrinsic mechanism in HGSC whereby chemotherapy itself amplifies chemoresistance and suggest that targeting chemotherapy-induced inflammation may help overcome treatment resistance.

immunology↗