Biology subjects

Fan, Y.

Publications and source records attributed to Fan, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Aptamer-Targeted PLGA Nanoparticles for Biofilm-Directed Intra-articular Antibiotic Delivery in Prosthetic Joint Infection

Introduction: Prosthetic joint infection (PJI) is a severe complication of orthopedic surgery, driven by biofilm-forming bacteria such as Staphylococcus aureus. Conventional antibiotics are limited in penetrating biofilms or remaining localized at the infection site. We engineered a targeted nanocarrier system by conjugating DNA aptamers specific to S. aureus biofilm components onto poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) encapsulating vancomycin. PLGA NPs were synthesized using flow-focusing microfluidics, followed by surface functionalization via EDC/NHS chemistry. Aptamer conjugation was validated using gel electrophoresis and DLS. Targeting efficiency and antimicrobial activity were evaluated through fluorescence microscopy, bacterial viability assays and in vitro biofilm models. Biodistribution and joint retention were assessed using fluorescent aptamer-conjugated NPs following intra-articular injection in rat knee joints. Results: The optimized vancomycin-loaded NPs exhibited uniform morphology, high vancomycin loading capacity (7.9 {+/-} 2.2%), and a sustained biphasic release profile with an early high-release phase followed by slower extended release. PK modeling indicated prolonged intra-articular drug retention with concentrations maintained above the minimum inhibitory concentration (MIC) for an extended period. Aptamer conjugation preserved nanoparticle stability and enhanced binding and retention within S. aureus biofilms in vitro, supporting improved biofilm localization. In-vivo fluorescence imaging demonstrated high local retention of aptamer-conjugated NPs, supporting localized joint retention with limited off-target tissue signal. Conclusions: S. aureus-specific aptamer conjugated nanoparticles (SA Apt-P(V)) represent a targeted intra-articular delivery platform with potential for localized PJI therapy. The combined in-vitro and in-vivo findings highlight their potential to improve local therapeutic concentration, minimize systemic exposure, and enhance infection control within prosthetic joints.

bioengineering↗

bioRxiv2026

Vascularized Organoids Emerge from a Heart-Foregut-like Intermediate Recapitulating Early Human Development

During early cardiogenesis, the heart regions lie in close contact with foregut endoderm, which supplies essential nutrients and signaling cues to orchestrate primitive heart tube assembly. Here, we show that self-organized heart/foregut like-structures emerge from human pluripotent stem cells (hPSCs). The initial heart/foregut-like structures, termed the Seed, are encased by surrounding supportive cells termed Soil, which provide a matrix microenvironment; the Seed progressively develops into chambered human cardiac organoids (hCOs) containing cardiomyocytes (CMs), epicardial cells, cardiac fibroblasts, and endothelial cells. Optimization of the induction system further enhanced hCO maturation and vascularization. Therefore, this Soil-Seed system provides a model to dissect human early heart/foregut self-organization.

developmental biology↗

bioRxiv2026

Timed binary WNT activity is sufficient to model the early human neural axis

The vertebrate nervous system develops into functionally distinct domains along the body axis[1]. Developmental studies implicate multiple signaling pathways in coordinating this process, but the order of specification events, sufficiency of individual signals, and molecular basis of competency remain unclear [2,3], leaving the field without a unified model of neuraxis patterning. Enteric nervous system (ENS) and midbrain dopaminergic (mDA) progenitors have reached clinical and preclinical testing [4-11], yet neither is produced at full purity, and yields vary markedly across human pluripotent stem cell (hPSC) lines, reflecting incomplete control of axial identity. Here we use single-cell genetic fate mapping to demonstrate that hPSCs can commit to anterior or posterior cranial fate within the first 24 hours of differentiation, before neural induction. Building on this finding, we show that the duration of a single saturating WNT pulse is sufficient to specify three 'first-order' domains: anterior cranial (0 h), posterior cranial (24 h) and trunk (48 h), each pre-neural and competent for CNS, neural crest and epidermal lineages. Nested 'second-order' domains are specified within first-order domains in response to WNT, FGF, and retinoic acid. Mechanistically, an anterior gene regulatory network repressing WNT targets is irreversibly shut down during the transition to posterior identities. Applying this binary WNT patterning logic, we generate mDA neurons and ENS progenitors robustly across hPSC lines and establish an assembloid model combining first-order progenitors to produce all major regions of the nervous system.

developmental biology↗

bioRxiv2026

Integrated Multiomics Reveals Intergenerational Brain Sensory System Remodeling Induced by Parental Intermittent Fasting

Intermittent fasting (IF) is increasingly recognized as a potent modulator of metabolic health, but its effects on brain function across generations remain poorly understood. Here, we show that parental IF, administered to both mothers and fathers before mating, is associated with coordinated molecular remodeling in the cerebral cortex of fathers and their offspring, with shared molecular signatures identified between these generations and a pronounced enrichment of sensory-associated pathways. Using whole-genome bisulfite sequencing, transcriptomic profiling, and proteomic analysis, we found that IF elicited widespread cortical epigenetic remodeling in fathers, accompanied by transcriptional and protein-level changes enriched for olfactory, taste, synaptic, and neurometabolic pathways. Strikingly, related molecular signatures were detected in F1 offspring that had never been directly exposed to fasting, consistent with intergenerational transmission of IF-associated cortical remodeling. Offspring responses were sex dependent, with female and male progeny exhibiting distinct patterns of DNA methylation, gene expression, and protein abundance. Integrated multiomic analyses identified conserved candidate networks involved in sensory perception, glutamatergic signaling, synaptic organization, intracellular trafficking, cytoskeletal regulation, and stress-response pathways. Together, these findings identify sensory-associated cortical remodeling as a prominent molecular feature associated with parental IF and reveal persistent, sex-dependent molecular alterations in the offspring brain.

genomics↗

bioRxiv2026

Structural Basis of γδ T-Cell Receptor Crosslinking and Activation by a Spontaneously Dimerized Fab

The gamma delta T-cell receptor ({gamma}{delta} TCR) mediates {gamma}{delta} T-cell responses that are crucial for immune defense, tissue surveillance, and homeostasis. While recent studies suggest that {gamma}{delta} TCRs engage ligands multivalently, how multivalent engagement activates the {gamma}{delta} TCR remains elusive. Here, we present the structures of the V{gamma}9V{delta}2 (clone G115) TCR in both the inactive and the agonist-crosslinked active states. In the {gamma}{delta} TCR lipoprotein complex, cholesterol and phospholipids form a "barrier" that isolates CD3{zeta}{zeta} from the other subunits and likely prevents autoactivation. As an agonist, the Fab fragment of the UCHT1 antibody dimerizes upon binding the V{gamma}9V{delta}2 TCR, thereby crosslinking and activating the receptor. Cryo-EM analysis of Fab-crosslinked V{gamma}9V{delta}2 TCR identifies three Fab dimer interfaces, one between the two light chains and the other two between light and heavy chains. These Fab-Fab interfaces, together with the Fab-CD3{epsilon} interface, mediate the assembly of the V{gamma}9V{delta}2 TCR and UCHT1 Fab into 2:2 tetramers. Upon activation, the V{gamma}9V{delta}2 TCR becomes conformationally plastic and loses enriched lipids, including cholesterol and phosphatidylethanolamine. Our findings reveal a dimerization-driven activation mechanism, inform the design of rigid TCR-crosslinking agonists, and suggest multivalency-induced clustering as a general paradigm for {gamma}{delta} TCR activation.

immunology↗

bioRxiv2026

Integrating Developmental Neurotoxicity Prediction with Adverse Outcome Pathway Reasoning

Experimental assessment of developmental neurotoxicity (DNT) is costly, time-consuming, and difficult to scale across large chemical inventories. New approach methodologies (NAMs), including computational approaches based on machine learning, deep learning, and large language models (LLMs), offer new ways to screen and prioritize chemicals. However, these emerging computational approaches have largely focused on predicting toxicity endpoints, with less attention to the mechanisms underlying those predictions. For DNT assessment, understanding this mechanistic basis is equally important. In this study, we integrated LLM inference with the adverse outcome pathway (AOP) framework to connect DNT predictions with plausible mechanisms. We constructed an AOP-informed benchmark linking ChEMBL target-activity measurements for 5,861 compounds to 14 AOPs representing five neurodevelopmental outcomes and evaluated ten LLMs for the prediction of molecular initiating events (MIEs), key events (KEs), key event relationships (KERs), and adverse outcomes (AOs), as well as the generation of mechanistic explanations. Explanation quality was evaluated using both a naive LLM judge and a rubric-based LLM judge. Across the zero-shot models, the highest observed macro-F1 scores were 0.818 for MIEs and 0.463 for AOs, but only 0.056 for KEs and 0.034 for KERs, identifying downstream pathway reconstruction as the principal challenge. Few-shot prompting substantially improved performance, with Gemini 3.8 Flash under four-shot prompting achieving macro-F1 scores of 0.956 for AOs, 0.813 for MIEs, 0.492 for KEs, and 0.457 for KERs. Both LLM-judge configurations indicated improved mechanistic explanation quality with few-shot examples, although strong outcome prediction did not consistently ensure recovery of the recorded pathway. Our results demonstrate the potential of AOP-informed LLMs to support DNT assessment by linking predicted neurodevelopmental outcomes to plausible biological mechanisms and enabling predictions to be evaluated at both the outcome and pathway levels.

pharmacology and toxicology↗

bioRxiv2026

AREION: A Foundation Model for Atlas-Agnostic Representation Learning of Brain Connectome

Brain foundation models have shown promising advances in learning generalizable representations from functional magnetic resonance imaging (fMRI) data. However, existing models are typically tied to specific brain atlases and cannot be applied to fMRI data represented using different atlases without full retraining, thereby severely limiting their broader utility across neuroimaging studies. To address this bottleneck, we introduce AREION, atlas-agnostic representation learning of brain connectomes. AREION overcomes atlas dependency through two integrated innovations. First, a Brain Region Contextualizing technique maps brain regions and connectivity entries from diverse atlases into a unified representation space based on their spatial, functional, and morphological characteristics. Second, a Hierarchical Brain Transformer Encoder processes region-specific connectivity profiles as variable-length token sequences and jointly captures local functional structure and global brain functional organization, conditioned on brain regional context, without assuming a fixed number of regions. Together, these two techniques enable the learning of generalizable representations across brain atlases with different parcellation resolutions and connectivity dimensions. AREION is pretrained on a large-scale multi-atlas cohort of fMRI data via self-supervised modeling and evaluated across diverse downstream tasks. Extensive experiments show that it outperforms strong supervised baselines and fMRI foundation models while using substantially fewer parameters, demonstrating strong transferability to atlases unseen during pretraining, generalization to external datasets, and excellent interpretability at the brain regional level.

neuroscience↗

bioRxiv2026

Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx

The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.

bioengineering↗

bioRxiv2026

Estrogen is Coupled to the Calcium Release Machinery in HumanLeiomyoma Cells

Uterine leiomyomas, commonly known as fibroids, are benign tumors of the female reproductive tract. They are the most common tumor of the female reproductive system and the leading cause of hysterectomy in the United States. Progesterone, estrogen, and their receptors are important drivers for the development and growth of leiomyomas. How estrogen drives leiomyoma growth remains unclear. We have previously shown that simvastatin can inhibit leiomyoma growth by modulating intracellular calcium. This suggests that calcium signaling is important for leiomyoma growth. We therefore hypothesized that estrogen may drive leiomyoma growth by stimulating calcium release through the membrane estrogen receptor GPR30 (also known as GPER). We found that estrogen dose-dependently induced calcium release in leiomyoma cells. The GPR30-specific agonist G-1 also induced calcium release, indicating that GPR30 mediates estrogen-mediated calcium release. The GPR30 antagonist G-15 blocked estrogen-induced calcium release and significantly reduced leiomyoma proliferation. Our results demonstrate that GPR30 is a major driver of estrogen-dependent growth in leiomyoma cells by modulating intracellular calcium. These findings may have high therapeutic relevance to leiomyomas and other estrogen-dependent tumors.

cell biology↗

bioRxiv2026

A targeted bispecific TGFBR2 antagonist antibody demonstrates cell selectivity and enhanced potency on human fibroblasts

Beyond its critical roles in development and tissue homeostasis, TGF{beta} signaling promotes key aspects of cancer progression and is a primary driver of fibrosis. Although blocking TGF{beta} signaling has great therapeutic potential for cancer and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), preclinical and clinical studies revealed that non-specific alteration of the pathway can have severe adverse consequences; therefore, inhibiting TGF{beta} signaling in a cell-type specific manner may avoid systemic toxic effects while preserving potential therapeutic effects. The parasitic helminth Heligmosomoides polygyrus has evolved cell-type-targeted modulators of TGF{beta} signaling. With insights from the development of other targeted signaling modulators and using the worm proteins as a guide, we sought to develop a human-fibroblast-targeted TGFBR2 antagonist. Here, we report mechanistic insights into the targeted worm TGFBR2 antagonist TGM6 and fusion proteins containing the TGM6 targeting domains. We created a bispecific antibody TGFBR2 antagonist that binds PDGFRA as a targeting receptor and demonstrates cell selectivity and enhanced potency in fibroblasts. Our findings suggest a viable path for developing targeted TGF{beta} signaling antagonists as therapeutics for cancer and tissue fibrosis.

cell biology↗

bioRxiv2026

Histone lysine demethylase inhibition is a disease-modifying therapy for hypertrophic cardiomyopathy

RationaleHypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder characterized by cardiac hypertrophy, fibrosis, arrhythmias, and sudden cardiac death (SCD). Although current therapies primarily target sarcomere dysfunction, the contribution of epigenetic dysregulation to HCM pathogenesis and its therapeutic potential remain poorly understood. ObjectiveTo determine whether pharmacological inhibition of histone lysine demethylases (KDMs) with JIB-04 can prevent or reverse HCM progression and to identify the underlying epigenetic mechanisms. Methods and ResultsWe evaluated the pan-KDM inhibitor JIB-04 in Myh6R403Q/+ mice carrying the murine equivalent of the pathogenic human MYH7 R403Q mutation. JIB-04 prevented disease progression, reduced cardiac hypertrophy and fibrosis, preserved cardiac function, and completely prevented SCD in cyclosporin A- accelerated HCM. JIB-04 also reversed established disease, produced sustained therapeutic benefits after drug withdrawal, and improved cardiac function in aged mice with spontaneous HCM. Bulk RNA sequencing and ATAC-seq demonstrated partial restoration of disease-associated transcriptional programs and chromatin accessibility. Proteomic analyses identified PHF2 (KDM7C) as a candidate target of JIB-04 in both mouse and human HCM hearts. PHF2 knockdown suppressed hypertrophic, inflammatory, and fibrotic gene expression in cardiomyocytes, macrophages, and fibroblasts, respectively. Human HCM hearts exhibited increased expression of multiple JIB-04-sensitive KDMs, including PHF2. In MYH7 R403Q induced pluripotent stem cell- derived cardiomyocytes, JIB-04 normalized disease-associated gene expression, restored connexin-43 membrane localization, and improved mitochondrial respiration. Although prolonged treatment induced reversible hepatomegaly with hepatic lipid accumulation, co-administration of the antioxidant N-acetylcysteine mitigated liver toxicity while preserving the therapeutic efficacy of JIB-04. ConclusionsPharmacological KDM inhibition prevents and reverses HCM through epigenetic remodeling of disease-associated transcriptional and chromatin programs. These findings identify KDM inhibition as a promising therapeutic strategy for HCM, establish PHF2 as a candidate mediator of disease pathogenesis, and support further development of KDM-targeted therapies.

physiology↗

bioRxiv2026

Interpretable Local-to-Global Estimation of Brain Aging Speed From Morphological Changes Using Longitudinal Structural MRI Data

Accurate characterization of brain aging is essential for understanding cognitive decline and assessing the risk of neurodegenerative disease. Brain age estimated from cross-sectional MRI provides a snapshot of brain health relative to chronological age, and the derived brain age delta has emerged as a promising biomarker. However, brain age delta reflects cumulative effects at a single time point and fails to capture ongoing aging dynamics. Longitudinal approaches address this limitation by estimating age differences between scan pairs to derive aging speed. Nevertheless, existing methods primarily rely on intensity or texture differences between image pairs, overlook the spatial heterogeneity of aging processes, and provide limited interpretability. To overcome these limitations, we propose a novel framework that estimates brain aging speed from longitudinal deformation fields obtained via diffeomorphic registration. Instead of solely generating a single global estimate, our method produces patch-wise local aging predictions and adaptively integrates them into a unified global prediction, improving both predictive performance and interpretability. Evaluated on large-scale datasets, our approach achieves superior accuracy compared with existing methods and enhances the identification of abnormal aging patterns in diseased populations. Code is available at https://github.com/Kateridge/Morphology-AgingSpeed.

neuroscience↗

bioRxiv2026

Discovering Heterogeneous Neurodegenerative Disease Patterns From MRI Data for Improved Prediction

Neurodegenerative diseases exhibit substantial heterogeneity, complicating both diagnosis and prognosis. Identifying clinically meaningful subtypes is crucial for understanding disease mechanisms and can also improve diagnostic precision and prognostic accuracy. Existing subtyping approaches primarily rely on unsupervised learning of patient data for capturing inter-individual variability, often failing to uncover subtypes that are informative for diagnosis or prognosis. To address this limitation, we propose a novel mixture-of-experts (MoE) framework that integrates predictive modeling with subtype identification. Unlike traditional subtyping methods, our approach learns a router to assign individuals to specialized expert networks, each corresponding to a distinct subtype, to improve predictive accuracy. This MoE framework ensures that the discovered subtypes are not only statistically distinct but also clinically informative. We evaluate the framework on a real-world dataset of mild cognitive impairment (MCI) subjects and a semi-simulated dataset, demonstrating superior performance for predicting MCI subjects progression to Alzheimers disease while identifying distinct clinically meaningful MCI subtypes. Code is available at https://github.com/Kateridge/MoESubtyping.

neuroscience↗

bioRxiv2026

Generative Modeling of Mouse Embryogenesis for Fate and Disease Prediction

Embryonic development is orchestrated by complex gene regulatory networks, and learning regulatory dynamics from developmental data could allow us to understand, predict, and ultimately engineer cell fates. Here we introduce Navigo (https://github.com/aristoteleo/Navigo-release), a biologically grounded generative modeling framework that learns a developmental vector field by integrating flow matching at the population level with RNA kinetics modeling at the molecular level. Navigo accurately maps developmental trajectories across lineages on a mouse embryogenesis scRNA-seq atlas spanning 43 time points and comprising 12.4 million cells. Applied to cardiac development, Navigo enables disease modeling by mechanistically resolving regulatory networks that distinguish congenital heart disease subtypes. Navigo also predicts perturbation effects in a zero-shot manner, as validated on independent in vivo data from six knockout genotypes without perturbation-specific training, uncovering lineage-specific gene-compensation mechanisms. Moreover, Navigo guides rational cell-fate engineering, exemplified by fibroblast reprogramming analyses, including identifying pro-fibrotic barriers to cardiac fates and evaluating hundreds of pairwise transcription factor combinations for neuronal fate, each consisting of one bHLH factor and one POU factor. Overall, Navigo provides a generalizable AI platform for perturbation-effect prediction, disease modeling, and rational cell-fate engineering, advancing toward AI-based virtual embryos for developmental biology and regenerative medicine.

bioinformatics↗

bioRxiv2026

Identifying Ecological Restoration Priority Areas through a Function-Structure-Dynamic Framework: Integrating Ecological Security Patterns and Future Land-Use Simulation in the Anhui Section of the Yangtze River Basin

Rapid urbanization has intensified ecological degradation and threatened ecosystem sustainability in the Yangtze River Basin. This study proposes a Function-Structure-Dynamic (FSD) framework integrating ecological protection importance assessment, ecological security pattern (ESP) construction, and future land-use simulation to identify ecological restoration priorities in the Anhui section of the Yangtze River Basin. Ecologically important areas were identified by coupling ecosystem services and ecological vulnerability. MSPA, landscape connectivity analysis, resistance surface modeling, and circuit theory were applied to construct the ESP, while the PLUS model simulated land-use change and ecological risks in 2032. Results identified 37 ecological sources covering 6,901.39 km{superscript 2} and 84 ecological corridors with a total length of 916.80 km. Ecological pinch points, barrier areas, and 17 ecological warning areas were further delineated. Based on these findings, four ecological restoration zones were proposed with differentiated management strategies. The FSD framework effectively integrates ecological functions, spatial structure, and future dynamics, providing scientific support for ecological restoration and sustainable territorial spatial planning in rapidly urbanizing regions.

ecology↗

bioRxiv2026

FERONIA-Dependent Translational Buffering of Ribosome-Associated Genes in Salt-Stressed Tomato Roots

Salt stress limits tomato productivity, yet how translational regulation contributes to root salt adaptation remains poorly understood. We integrated RNA-seq and ribosome profiling in wild-type (WT) and fer tomato roots under control and 150 mM NaCl conditions. In WT roots, the salt response was predominantly transcript-driven, but a 29-gene ribosome-associated module showed reduced RNA abundance alongside increased translational efficiency (TE), indicating selective translational buffering. FER deficiency disrupted this balance: it constitutively elevated ribosome occupancy of ribosome-associated genes while reducing basal expression of stress- and ion-transport-related genes. Under salt treatment, fer further showed stronger ion-transport transcriptional responses but weaker ribosome-associated TE responses, consistent with impaired translational selectivity. WT salt stress also shifted ribosome allocation away from the 5'UTR toward the CDS, an effect attenuated in fer; upstream open reading frame (uORF) and coding sequence (CDS) translational efficiency were also positively coupled during salt treatment. Feature modelling confirmed established features associated with uORF translation and further identified weaker local RNA folding around the uORF start codon, proline and charged amino acid enrichment, and TAG or TGA stop codon identity as positive predictors. Together, these results reveal FER-dependent changes in ribosome-associated translational buffering during tomato root salt responses.

Plant Biology↗

bioRxiv2026

STN-DBS frequency-tuned beta subband dynamics are associated with speech tempo in Parkinson's disease

In Parkinsons disease, subthalamic nucleus deep brain stimulation (STN-DBS) frequency modulates narrow beta subbands, with low-frequency stimulation (LFS) selectively attenuating 15-23 Hz power. The negative association between this subband and speech tempo, together with the LFS-related improvement in articulatory rate, suggests that 15-23 Hz subband dynamics may serve as a candidate neural marker associated with speech tempo modulation.

neuroscience↗

bioRxiv2026

Mono-ADP-ribosylation-driven immunosuppression and cross-resistance to therapy through cancer cell intrinsic and extrinsic mechanisms

Mono-ADP-ribosylation (MARylation) is emerging as an important regulator of anti-cancer immunity and immunosuppressive tumor microenvironment (TME). Our previous studies showed that PARP11, one of several enzymes that facilitate MARylation, regulates the activities of intratumoral cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Here, we demonstrate that stimuli such as adenosine, epinephrine, or glucagon-like peptide-1 (GLP1) induced PARP11 in cancer cells. Upregulation of PARP11 in cancer cells led to PARP11-mediated MARylation, ubiquitination, and accelerated degradation of MHC-I through the autophagy-lysosomal pathway. Induction of PARP11 protected cancer cells from killing by specific CTLs and stimulated tumor growth and progression. Genetic ablation of PARP11 attenuated MHC-I MARylation, ubiquitination, and interaction with autophagy receptors. Pharmacologic inhibition of PARP11 in pancreatic ductal adenocarcinoma (PDAC) cells restored their MHC-I levels, sensitized them to killing by CTLs, inhibited tumor growth, and impeded their initial resistance to chemotherapy and their acquired resistance to targeted therapy with RAS inhibitors. Moreover, inhibition of PARP11 prevented hyperprogressive disease in a mouse melanoma model treated with immune checkpoint inhibitors (ICBs), suggesting that PARP11 is a major therapeutically actionable driver of immunosuppression in tumors. SYNOPSISInduction of PARP11 in the tumor microenvironment mediates immunosuppression. This study reports that PARP11-driven MARylation and ubiquitination of MHC-I in cancer cells drives immune evasion, tumor growth and resistance to therapies.

cancer biology↗