Biology subjects

Huang, G.

Publications and source records attributed to Huang, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence

Metastatic prostate cancer remains a lethal disease, with most treatments focusing on the androgen receptor (AR) axis. We identified the zinc finger protein 281 (ZNF281) as a previously unrecognized driver of metastatic prostate cancer that promotes both AR-related transcriptional output and distinct AR-independent tumor-promoting pathways. It increases AR expression and acts as a coactivator to promote AR transcriptional activity. Independent of AR, ZNF281 promotes prostate cancer by upregulating SMURF1 to sustain tumor growth and by promoting SNAIL-mediated metastasis. We developed an orally bioavailable, ZNF281 Interfering Molecule (Oral ZIM) that disrupts its DNA binding and AR protein interaction. Knockout of ZNF281 as well as treatment with oral ZIM potently inhibited prostate cancer growth and metastasis in orthotopic xenograft models of castration-sensitive and castration-resistant prostate cancers (without detectable systemic toxicity), and ZIM outperformed enzalutamide treatment in patient-derived prostate cancer organoids.

cancer biology↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

Deep learning-based identification and quantification of rare circulating hybrid cells in orthotopic pancreatic cancer models

SignificanceRare-cell identification in fluorescence microscopy remains challenging because targets are sparse and background varies between specimens. Combining specimen-specific fluorescence enrichment with image classification may enable efficient and more specific automated detection of rare cells. AimWe developed a two-stage framework to identify and quantify candidate rare circulating hybrid neoplastic cells (CHCs, ECAD+/CD45+) in peripheral blood mononuclear cell (PBMC) preparations from tumor-bearing and tumor-naive mice. ApproachPBMCs from 28 mice were imaged by multichannel fluorescence microscopy. Matched unstained samples established animal-specific ECAD and CD45 background distributions for candidate cell enrichment. Blinded multi-annotator consensus labels were used to train a convolutional neural network (CNN) from DAPI, ECAD, and CD45 image crops. Generalization was evaluated by leave-one-animal-out validation across 10 random initializations. Final classification used a 10-model ensemble, and rare-cell burden was compared between groups using negative-binomial regression with total segmented-cell count as an exposure. ResultsOf the 1,065,512 segmented cells, enrichment retained 10,176 candidates (0.96%), reducing the search space by >99%. Four of five evaluable tumor-bearing animals showed reproducible held-out discrimination, with median quantified area under the receiver operator characteristic curve (AUROCs) of 0.918-0.951; one animal was a reproducible outlier (median AUROC, 0.338). Ensemble deployment identified 157.94 positive-consensus cells per 50,000 segmented cells in tumor-bearing animals versus 49.55 in controls. The estimated rare-cell rate was 3.15-fold higher in tumor-bearing animals (95% CI, 0.91-10.99; two-sided p=0.071; prespecified one-sided p=0.036). ConclusionsSpecimen-specific fluorescence enrichment combined with supervised image classification reduced the cellular search space and enabled automated quantification of a rare CHC (ECAD+/CD45+) phenotypes. Cross-animal validation also identified specimen-specific generalization failure, highlighting the importance of biological-specimen-level validation.

cancer biology↗

bioRxiv2026

A longevity-associated ubiquitin E3 ligase UBE3C governs lamin B1 homeostasis through selective autophagy and delay senescence

Nuclear lamina integrity is fundamental to cellular homeostasis across the lifespan 1, and its progressive deterioration is closely linked to human aging 2. Yet, the regulatory mechanism that govern this decline and how they might be counteracted in long-lived individuals remain poorly defined. Here, by combining whole-exome sequencing of Ashkenazi Jewish centenarians with GTEx transcriptomes, we identify ubiquitin E3 ligase UBE3C strongly associated with exceptional longevity and progressively declines with age across human tissues. UBE3C knockdown triggers premature senescence and destabilizes key nuclear lamina components Lamin B1 (LMNB1) and Lamin B receptor (LBR), while the longevity-associated UBE3C variant delays senescence and preserves LMNB1/LBR expression. Mechanistically, UBE3C interacts directly with LMNB1/LBR and modulates their abundance via selective autophagy. Notably, we uncover the ER- resident autophagy trigger CKAP4 3 bridges UBE3C and LMNB1. UBE3C loss enhances LMNB1-CKAP4 binding, linking nuclear lamina turnover to autophagy. Together, our findings establish UBE3C as a central guardian of nuclear lamina maintenance during senescence and offering novel insights into interventions against age-related nuclear lamina deterioration.

cell biology↗

bioRxiv2026

Brassinosteroid-auxin crosstalk shapes rice flag leaf angle to boost dense planting yield

Flag leaf angle (FLA) critically determines rice yield potential under dense planting conditions. As two pivotal phytohormones determine rice FLA, the antagonistic interaction between brassinosteroid (BR) and auxin remains largely uncharacterized. We here demonstrate that BR signaling reduces auxin biosynthesis to control FLA via regulating the biosynthesis of secondary cell wall (SCW). Genetic evidence demonstrates OsYUC8 mutants disrupt SCW formation, leading to increased FLA. At the molecular level, the BR-related transcription factor OsBZR1 directly binds to and represses OsYUC8 promoter activity, thereby fine-tuning auxin-mediated SCW biosynthesis. Field evaluations reveal that osbzr1 mutants display optimized flag leaf architecture and improved yield performance under high-density cultivation. Our study not only delineates the antagonistic BR-auxin interaction governing FLA but also establishes a genetic strategy for manipulating crop architecture to maximize yield in dense planting conditions. One-sentence summaryOsBZR1-mediated repression of OsYUC8-driven auxin biosynthesis modulates secondary cell wall formation to optimize flag leaf architecture, providing a genetic strategy for maximizing yield under high-density cultivation.

plant biology↗

bioRxiv2026

Ms4a4a loss reprograms amyloid-associated microglia and limits dense-core plaque-associated tau spreading

INTRODUCTIONMicroglia regulate amyloid plaque-associated microenvironments that contribute to downstream tau pathology in Alzheimers disease (AD). Variants within the MS4A locus are strongly associated with AD risk and resilience and are linked to microglial biology; however, the functional role of MS4A4A in plaque-associated tau pathology remains poorly understood. METHODSSingle-nucleus RNA sequencing (snRNA-seq) was performed on hippocampi from non-transgenic, Ms4a4a knockout (4A-KO), 5xFAD, and 5xFAD 4A-KO mice at 6 months of age. To assess plaque-associated tau pathology, AD-derived tau aggregates were injected into the hippocampus of 5xFAD and 5xFAD 4A-KO mice at 6 months, and histological analyses were performed 3 months later. RESULTSAmyloid pathology was the dominant driver of microglial state transitions, while Ms4a4a loss selectively remodeled activated microglial transcriptional programs enriched for interferon, lysosomal, autophagic, and proteostatic pathways. Activated microglia from 5xFAD 4A-KO mice exhibited altered expression of genes linked to immune signaling and protein handling. Following AD-tau inoculation, Ms4a4a loss did not significantly alter overall phospho-tau burden but selectively reduced dense-core plaque-associated neuritic plaque tau (NP-tau), particularly in the contralateral hemisphere. This phenotype was strongest surrounding X-34-positive fibrillar plaques and occurred without major changes in plaque-associated microgliosis. DISCUSSIONThese findings identify Ms4a4a as a regulator of plaque-associated microglial programs linked to NP-tau accumulation in the amyloid-bearing brain. More broadly, this work supports a model in which AD resilience-associated microglial pathways selectively shape plaque-associated microenvironments that promote downstream tau pathology.

neuroscience↗

bioRxiv2026

The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimers disease and Parkinsons disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

neuroscience↗

bioRxiv2026

Genetically informed single-cell and spatial mapping of metabolic programs in human health and disease

Defining cell-type-specific endogenous metabolic features, the spatial distribution of cell-level metabolic states and cellular responses to exogenous metabolites is very important for understanding disease mechanisms. However, existing transcriptome-based metabolic models primarily infer intracellular reaction or pathway-level activities, and therefore cannot directly assess associations between individual metabolite levels and cellular states, particularly for metabolites that act extracellularly as signalling molecules rather than entering cells as metabolic substrates. To overcome this problem, we introduce the gmMAP (Genetically informed metabolite trait mapping across single-cell and spatial tissues), a framework that integrates metabolite GWAS summary statistics with single-cell and spatial transcriptomes to map metabolic programmes at cellular and spatial resolution. Notably, the gmMAP enables the prediction of endogenous metabolic process activation while also revealing intrinsic associations between exogenous metabolites and diverse cellular functional states. To further capture the connectivity of cellular metabolic networks, we incorporated a constraint-based metabolic flux model to evaluate global metabolic activity. To evaluate the accuracy and generalizability of gmMAP, we applied the framework across representative biological contexts spanning human development, physiological homeostasis, inflammation and cancer. In human kidney development, the gmMAP captured dynamic metabolic programmes, which was validated using paired transcriptomic and metabolomic reference datasets, supporting its reliability in metabolite identification and metabolic-flow inference. At the organ level, the gmMAP reconstructed spatial metabolite distribution patterns across 17 mouse organs under homeostatic and autoimmune inflammatory conditions, and further extension of gmMAP to 24 normal human tissues generated a multi-scale metabolic atlas at both organ and cellular resolutions. In disease settings, gmMAP revealed metabolic reprogramming across 29 pan-cancer cell populations, and identified potential links between exogenous metabolites and inflammation-associated stromal metabolic remodelling in ulcerative colitis. Together, gmMAP can consistently connect genetically informed metabolite traits with cell states, spatial tissue organization and disease pathology.

genomics↗

bioRxiv2026

Single-nucleus Transcriptomics Reveals Precystic Dysfunction in Polycystic Kidney Disease

Polycystic kidney disease (PKD) is the most common cause of end stage renal disease with a known genetic etiology. This disease is characterized by the progressive development and expansion of kidney cysts. While recent studies have shed light on cell types and states contributing to PKD progression following cyst formation, the biological processes at work prior to cyst formation are relatively unexplored. To better understand mechanisms contributing to cystogenesis, we analyze pre-cystic kidneys from Pkd1R3277C/R3277Cmice across multiple early timepoints, generating a transcriptomic atlas of nearly 1 million single nucleus transcriptomes. Activation of a small subset of genes in a precystic signaling pathway drives changes in both the distal convoluted tubule and proximal tubule cells. This pathway overlaps with a recently described "failed repair" transcriptomic signature despite the lack of clear changes in tissue morphology at these early stages of nascent cystogenesis. We identify Creb5 as a critical driver for cystogenesis. This single cell transcriptomic analysis of nascent cystogenesis reveals previously unrecognized cellular signaling at the earliest assessed points in precystic kidneys and provides a foundation for the development of high definition early diagnostic and therapeutic approaches prior to observable cysts in PKD.

Developmental Biology↗

bioRxiv2026

BBB-Permeable Near-Infrared Oxazine Fluorophores for White Matter Tract Imaging

Preserving critical functional tissue remains a major challenge in fluorescence-guided surgery (FGS), particularly in neurosurgery where injury to white matter tracts can lead to lasting neurological deficits. Probes for preventing iatrogenic injury of the peripheral nervous system have highlighted the potential of real-time intraoperative guidance for nerve-sparing surgery, supporting improved preservation of critical functional tissue, but analogous tools for the central nervous system remain limited. While there are some awake mapping and MRI based techniques that try to minimize the resection of white matter tracts (WMTs), they do not provide surgeons with real-time visualization. To address this gap, we rationally translated a peripheral nerve targeted oxazine fluorophore platform into a library of novel oxazine dyes that can penetrate the blood-brain barrier (BBB), exhibit specificity for white matter tissue and maintain spectral compatibility with clinically relevant imaging systems. Guided by our fluorophore medicinal chemistry platform, this work includes library design, photophysical property characterization, in vivo WMTs specificity screening, and in vivo imaging window assessment of the lead candidates to evaluate neurosurgical workflow compatibility. The lead candidate identified from this library demonstrated strong in vivo WMTs-specific fluorescence intensity, contrast and imaging window compatible with neurosurgical workflows, establishing BBB-permeable oxazine fluorophores as a promising scaffold for future structure-sparing neurosurgical FGS.

bioengineering↗

bioRxiv2026

EEG-Neurofeedback Targeting Gamma Oscillations at the Parieto-Occipital Region Reduces Pain Perception

Pain is closely associated with both spontaneous and stimulus-evoked gamma oscillations, which differ in their phenomenology and their relationship to pain perception. These associations make gamma oscillations a promising target for pain interventions, such as closed-loop real-time neurofeedback (NFB). While modulating stimulus-evoked gamma oscillations is technically challenging due to their concurrent occurrence with pain perception, targeting spontaneous gamma oscillations is both feasible and practical, as it could influence subsequent cortical nociceptive processing and reduce pain. To test this mechanistic hypothesis, we developed a novel NFB training protocol aimed at increasing spontaneous gamma oscillations in the parieto-occipital region to alleviate pain. Eight-eight healthy, right-handed subjects were randomly assigned to either an active or sham NFB group and completed three sessions of NFB training. During each session, subjects underwent EEG recording and received randomized laser stimulation while watching a video. After three training sessions, approximately 52% of subjects in the active group successfully increased the spectral power of spontaneous gamma oscillations in the parieto-occipital region. Crucially, the spectral power of spontaneous gamma oscillations was significantly and negatively correlated with subjective pain intensity after the third NFB session. Additionally, subjects who responded successfully to active NFB showed significant reductions in pain intensity, unpleasantness, and laser-evoked potentials compared to the sham group. Together, these findings establish a causal relationship between spontaneous gamma oscillations in the parieto-occipital region and pain perception, potentially offering a novel NFB-based therapeutic strategy for pain management.

neuroscience↗

bioRxiv2026

cGAS bends unpaired DNA to form an unconventional structure that hyperactivates the innate immune response

cGAS is a pattern-recognition receptor for dsDNA and forms 2cGAS:2DNA dimers followed by oligomerization into phase-separated condensates when fully-complementary DNA is studied. However, many DNAs are not fully complementary. We report that DNA with unpaired regions such as those found during transcription, recombination or replication (designated as bubble-DNA, Bu-DNA) causes cGAS hyper-activation. Hyperactivation is observed by Bu-DNA embedded in linear DNA, circular DNA, plasmid DNA and mitochondria DNA. Bu-DNA binds significantly more tightly to the cGAS catalytic domain than paired-DNA but suppresses condensation. Cryo-EM and single-molecule FRET reveal that cGAS forms 2cGAS:1DNA complexes by bending Bu-DNA into a V-shape using the unpaired region as a hinge, limiting its oligomeric state. This uncovers a novel mode of cGAS activation attributed to pattern diversity within pattern ligands.

immunology↗

bioRxiv2026

Toward CT-based Tractography: Presurgical White Matter Tract Mapping in Intracerebral Hemorrhage

Presurgical mapping of key white matter (WM) fiber tracts is crucial for intracerebral hemorrhage (ICH) surgery, but it currently relies on tractography from diffusion MRI (dMRI), which has limited applicability in urgent or resource-constrained settings due to long scan times and limited MRI availability. To bridge this gap, we developed a deep learning approach designed to reconstruct critical fiber tracts directly from routinely acquired CT scans, focusing on the corticospinal tract (CST) due to its high clinical relevance. By training a novel network on a curated dataset of 150 paired CT-dMRI scans (101 ICH patients and 49 healthy subjects), we enabled the direct mapping of the CST from CT images alone, bypassing the traditional requirement for dMRI. Our results demonstrate that the CT-derived tracts achieve high anatomical plausibility, with neurosurgeon expert assessments yielding a Likert score of 3.64. Furthermore, the clinical relevance of these reconstructions was validated by a significant correlation between CT-derived tract integrity and patient motor scores (r = 0.726, p = 3.731x 10-7). These findings suggest that in complex clinical scenarios, particularly where dMRI signal quality is compromised by lesion-induced distortion, this CT-based mapping may serve as a useful anatomical reference. Overall, by enabling CT-based WM mapping, our method potentially offers a practical route to gain the key advantages of tractography in resource-limited or time-critical settings

neuroscience↗

bioRxiv2026

Cell fusion reprograms tumor cells and promotes RUNX1-mediated invasion and dissemination in colorectal cancer

Metastasis remains the primary cause of cancer-related morbidity and mortality, despite significant advances in targeted therapies. Although metastatic dissemination requires tumor cells to escape the primary lesion and colonize distant organs, the mechanisms by which primary tumor cells gain metastatic competence remain poorly understood. Increasing evidence demonstrates that fusion of tumor (i.e., neoplastic) and immune (e.g., macrophages) cells generate a distinct population of tumor-immune hybrid cells with enhanced functional ability to migrate and disseminate into peripheral blood. Herein, our study investigates tumor-macrophage hybrid cells, an underexplored population of disseminated tumor cells, and their inherent heterogeneity and acquisition of molecular mechanisms underlying their dissemination as metastatic effectors in colorectal cancer (CRC). Through hybrid cell phenotyping utilizing integrative single-cell RNA sequencing (scRNA-seq), cyclic immunofluorescence (cyCIF) and functional assays with an in vitro model of CRC hybrid cells, we identify Runt-related transcription factor 1 (Runx1) as a central regulator of hybrid cell motility and invasion. Runx1 depletion in hybrid cells suppressed functional protease expression, chemotactic activity and extracellular matrix (ECM) invasion. Furthermore, pharmacologic inhibition of RUNX1 in an in vivo model reduced hybrid tumor growth and dissemination into peripheral blood, key attributes of metastatic spread of disease. In patients with CRC, RUNX1+ hybrid cells were identified in both primary tumor and peripheral blood, where circulating hybrid cells (CHCs) exhibited enriched migratory and epithelial-to-mesenchymal transition (EMT) phenotypes. Taken together, these findings reveal a mechanistic role for RUNX1 in driving invasive behavior of tumor-immune hybrids and highlight disseminated CHCs as an under-recognized contributor to metastatic spread and a promising noninvasive biomarker for tumor progression.

cancer biology↗

bioRxiv2026

Mechanistic insight into the phosphorylation of ERK by MEK

The RAS-RAF-MEK-ERK cascade regulates critical cellular processes such as cell proliferation and differentiation, with its dysregulation driving over 30% of human cancers. However, the active state of MEK and molecular mechanisms of ERK phosphorylation remain unclear. Here, we report the cryo-EM structures of phosphorylated MEK1 (pMEK1) bound to unphosphorylated and monophosphorylated ERK1. These structures reveal that pMEK1 interacts with ERK1 via three interfaces: first between MEK1 N-terminal peptide and ERK1 D-site recruitment site (DRS), second between MEK1 C-lobe and ERK1 F-site recruitment site (FRS), and third between MEK1 activation loop and ERK1 activation loop. Notably, we identify an unexpected phosphorylation mechanism: pMEK1 catalyzes ERK1 T202 phosphorylation through phosphate transfer from ERK1 Y204. In addition, pMEK1 exhibits phosphatase activity, catalyzing the dephosphorylation of ERK1 Y204. These findings allow us to delineate the catalytic cycle of MEK-catalyzed ERK phosphorylation and provide insights for targeting this oncogenic pathway.

molecular biology↗

bioRxiv2026

Aberrant oxidative metabolism selects for TET2-deficient hematopoietic stem and progenitor cells

The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2. Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2-deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2-deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2-deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage. Statement of SignificanceThis study identifies oxidative metabolism as a critical driver of selection for TET2-deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.

cancer biology↗

bioRxiv2026

IR-B deficiency and fatty acid dysregulation accelerate prostate cancer progression via PI3K/AKT signaling

The insulin receptor (IR) is markedly overexpressed in both human and mouse prostate cancer, with a significant elevation in the IR-A/IR-B ratio across patient tissues, cell lines, and Hi-Myc mouse prostates. To elucidate the role of IR-B in prostate tumorigenesis, we generated a prostate-specific IR-B knockout (KO) mouse model using Pbsn-Cre-driven recombination. Prostate-restricted loss of IR-B was confirmed at the transcript level and did not affect other tissues. Crossing these mice with Hi-Myc transgenics revealed that IR-B deficiency promotes accelerated progression to invasive adenocarcinoma, characterized by enhanced cellular proliferation and atypical histopathology. Transcriptomic and metabolomic profiling of dorsolateral prostate lobes demonstrated activation of PI3K/AKT and mTOR signaling, along with upregulation of IRS1/2/4 and IGF2. Metabolite analyses indicated elevated fatty acid levels and enhanced lipolysis pathways, implicating metabolic reprogramming in tumor progression. Notably, glucose and lipid metabolism genes, including GLUT1, GLUT12, FASN, and GPR120, were upregulated, accompanied by an increased BCL2/BAX ratio, suggesting apoptosis inhibition. Functional studies further revealed opposing roles of dietary fatty acids: {omega}-3 polyunsaturated fatty acids (EPA, DHA) suppressed prostate cancer cell survival, proliferation, and PI3K/AKT signaling while promoting apoptosis, whereas {omega}-6 fatty acid (arachidonic acid) exerted pro-tumorigenic, anti-apoptotic effects. Collectively, these findings identify IR-B loss as a driver of metabolic and signaling reprogramming that accelerates prostate tumorigenesis, while highlighting {omega}-3 fatty acids as potential modulators counteracting IR-B-deficient prostate cancer progression.

cancer biology↗

bioRxiv2026

Myeloid CD209 impairs T-cell activation by inducing ICAM-2-ERM-dependent cortical stiffening

Resistance to PD-1-based immunotherapy remains a major challenge in cancer treatment, especially in immunologically "cold" tumors characterized by T-cell exclusion and impaired effector function. Tumor-associated myeloid cells are important mediators of this resistance, but whether they directly suppress T-cell immunity through mechanical regulation remains unclear. Here, we identify DC-SIGN (CD209), a myeloid-expressed C-type lectin receptor, as a mechanosuppressive regulator of antitumor T-cell immunity. DC-SIGN is selectively enriched in tumor-infiltrating M2-like macrophages and monocytes, and its expression is associated with poor clinical response to PD-1 blockade and elevated TIDE scores across multiple cancer types. Mechanistically, DC-SIGN directly engages ICAM-2 on T cells and activates ROCK1-ERM signaling. This interaction increases T-cell cortical stiffness, destabilizes T cell-antigen-presenting cell interactions, and attenuates T-cell receptor signaling. Blocking the DC-SIGN-ICAM-2-ERM pathway restores T-cell activation and promotes CD8+ T-cell infiltration and effector function in mouse, humanized, and ex vivo human tumor systems. Importantly, DC-SIGN blockade overcomes resistance to PD-1-based immunotherapy in refractory and immunologically "cold" tumor models, and further enhances the response to PD-1 inhibition. Together, our findings define a myeloid-derived mechanical immune checkpoint and reveal T-cell mechanosuppression as a targetable mechanism of tumor immune evasion and immunotherapy resistance.

immunology↗