Biology subjects

Liu, L.

Publications and source records attributed to Liu, L..

At least 253 records · Page 14Linked to original sources

bioRxiv2025

Adolescents with major depression featured by sensory-association subtyping show divergent information dynamics and streams

Adolescent major depressive disorder (MDD) exhibits complex and heterogeneous alterations of brain functional organization. To understand the neurobiological basis of adolescent MDD, we adopted resting-state functional MRI data and used various matrix decomposition approaches to obtain the organization gradients, temporal dynamics, and information streams. With clustering sensory-association gradient features in our exploratory sample (NMDD = 250 and NControls = 203), we identified two MDD subtypes. Subtype 1 was characterized by sensory contraction and subtype 2 was associated with association expansion. In addition, two subtypes showed divergent bottom-up and top-down information flows in sensory and association areas using temporal dynamics analysis. These subtypes exhibit distinct age-related changes and reorganization trajectories along sensory-association and auditory-visual axes, highlighting that cortical information flow patterns systematically vary and relate differently to sensory integration, cognitive complexity, and aging. These network distinctions are linked to clinical severity and molecular mechanisms. Subtype 1 is predominantly associated with early neurodevelopmental abnormalities and emotional regulation deficits, while Subtype 2 is more related to synaptic dysfunction and reduced neuronal excitability. These results could be largely replicated in another independent sample (NMDD = 73 and NControls = 28). We therefore construct a sensory-association dual functional framework to characterize MDD heterogeneity in adolescent MDD. Itl integrates cortical hierarchy, developmental trajectories, and genetic influences, offering novel insights into MDD pathophysiology and providing a theoretical foundation for precision psychiatry, facilitating personalized diagnosis and intervention strategies.

neuroscience↗

bioRxiv2025

HDL Nanodiscs Loaded with Liver X Receptor Agonist Decreases Tumor Burden and Mediates Long-term Survival in Mouse Glioma Model

Glioblastoma multiforme (GBM) is highly aggressive primary brain tumor with a 5-year survival rate of 7%. Previous studies have shown that GBM tumors have a reduced capacity to produce cholesterol and instead depend on the uptake of cholesterol produced by astrocytes. To target cholesterol metabolism to induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists and CpG oligonucleotides for targeting GBM were investigated. LXR agonists synergize with sHDL nanodiscs by increasing the expression of the ABCA1 cholesterol CpG oligonucleotides are established adjuvants used in cancer immunotherapy that work through the toll-like receptor 9 pathway. In the present study, treatment with GW-CpG-sHDL nanodiscs increased the expression of cholesterol efflux transporters on murine GL261 cells leading to enhanced cholesterol removal. Experiments in GL261-tumor-bearing mice revealed combining GW-CpG-sHDL nanodiscs with radiation (IR) therapy significantly increases median survival compared to GW-CpG-sHDL or IR alone. Furthermore, 66% of long-term survivors from the GW-CpG-sHDL +IR treatment group showed no tumor tissue when rechallenged.

cancer biology↗

bioRxiv2025

Targeted Protein Degradation by KLHDC2 Ligands Identified by High Throughput Screening

Proteolysis targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high throughput screening.

biochemistry↗

bioRxiv2025

The lysine side chain's swing motion in AapA1 toxin promotes water transport through transmembrane pores

The rising antibiotic resistance of Helicobacter pylori and the emergence of multi-drug-resistant strains pose significant challenges to its eradication. Understanding the molecular mechanisms driving this resistance is critical. This study investigates how AapA1, a toxin protein, may inhibit H. pylori growth and cause morphological changes by forming transmembrane pores in its inner membrane. Using experimental data and molecular dynamics simulations, we analyzed the pore structure and its formation mechanism. Results show that AapA1 forms pores on liposomes and exists stably in the membrane as -helices through different multimers, creating hydrophilic pores of varying sizes. Dynamic oscillation of K16/23 side chains in the membrane affects water transport through these pores, and restricting their movement significantly reduces transport. AapA1 monomers adopt three distinct conformations, with the K16/23 residues showing an up-down swing motion, potentially facilitating accelerated transport of substances. This study provides a new perspective on the dynamic structure-function relationship of AapA1-membrane interaction and highlights the role of positively charged residues in AapA1. Understanding the multimeric AapA1-membrane structure and the mechanism underlying AapA1-induced transmembrane pores is particularly crucial to develop new drugs and treatment options to reduce drug resistance emergence and combat any new emergence development.

biophysics↗

bioRxiv2025

Altered Interpersonal Neural Synchronization during Social Interaction After Shared Excluded Experiences in Depressed Adolescents

BackgroundMajor depressive disorder (MDD) is common in adolescents, and the special development stage, during which adolescents brain and neuroendocrine system develop intensively, makes it subtly difficult to develop prevention and treatment strategies for depressed adolescents compared with depressed adults. Meanwhile, public psychosocial stressors significantly influence adolescents mental health and social interaction, rendering it essential to explore how a shared psychosocial stressor, i.e., shared excluded experiences, influences social interaction in depressed adolescents. MethodsWe designed a 4-player cyberball game to probe adolescents responses to shared excluded experiences and explore the underlying interpersonal neural synchronization (INS) with functional near-infrared spectroscopy (fNIRS). ResultsWe found that shared excluded experiences could enhance adolescents social interaction preferences but decreased INS in each pair of excluded adolescents, which indicates a reduced willingness to interact with others after the exclusion. However, no significantly different behavioral responses to the shared excluded experiences were found in depressed adolescents compared to adolescents as healthy controls (HC). Further analyses revealed that adolescents with MDD experienced more negative feelings than HC after exclusion. Of note, adolescents with MDD demonstrated stronger INS than HC, indicating the potential empathic stress in depressed adolescents. In addition, there existed altered brain-behavioral association patterns in responses to shared excluded experiences in depressed adolescents. ConclusionsIn summary, our study gives us deeper insights into how a shared psychosocial stressor impacts the INS in depressed adolescents, and it might be demonstrated that INS could be more sensitive than behavioral responses to detect social interaction deficits in depressed adolescents.

neuroscience↗

bioRxiv2025

Retinoic acid signaling guides the efficiency of inner ear organoid-genesis and governs sensory-nonsensory fate specification

Inner ear organoid development--from germ layer to otocyst formation--relies on timed chemical cues to recapitulate major signals in vivo. In contrast, later stages of differentiation--from otic vesicle (OV) to organoid formation--are self-guided, even though these stages are modulated by several key morphogens in vivo. We sought to elucidate additional morphogens that might improve culture efficiency and influence cell fate decisions. Using a whole-transcriptomic approach, we identified major differences in native and stem cell-derived OVs related to anterior-posterior patterning and retinoic acid (RA) signaling. Increasing the level of RA during OV formation in these cultures modulated organoid efficiency, increased nonsensory markers, decreased sensory markers, and decreased hair cell production. The organoid culture platform mimics the exquisite RA sensitivity found in normal inner ear development and may help identify RA-responsive genes driving organogenesis and cell fate specification.

neuroscience↗

bioRxiv2025

CD45-mediated apoptosis and IL2R downregulation by serine proteases from diarrheagenic bacteria

Most enteropathogens secrete one or more members of the serine protease autotransporters of Enterobacteriaceae (SPATE). We previously demonstrated that SPATE cleaves various O-linked glycoproteins on leukocytes, including the tyrosine phosphatase CD45RO. SPATE impairs leukocyte functions and triggers apoptosis in activated T cells in vitro. Here, we show that SPATE produced by pathogenic E. coli, Shigella, and the mouse pathogen Citrobacter rodentium cleaves not only CD45RO but also CD45 isoforms containing exons A and B. We found that the cleavage of CD45 in primary T cells from both human and murine sources correlated with decreased IL2RA (CD25) surface expression in a concentration-dependent manner. SPATE did not cleave CD25 or affect T cell activation. However, SPATE requires CD45 expression for the depletion of CD25 in activated T cells, as SPATE did not significantly impact CD25 in the Jurkat J45.01 cell line, which lacks CD45. More importantly, we discovered that J45.01 cells resisted SPATE-mediated apoptosis, whereas apoptotic wild-type Jurkat cells exhibited decreased surface expression of CD25. Furthermore, we observed that mice infected with C. rodentium lacking SPATE displayed lower mortality, delayed intestinal colonization, reduced inflammatory cytokines, and decreased leukocyte infiltration in the lamina propria while having a higher number of CD25+ T cells compared to mice infected with wild-type CR or the CR SPATE mutant expressing Crc2 in trans. Our data suggest that SPATE-producing pathogens trigger T-cell apoptosis through CD45 via a mechanism akin to IL2 deprivation, demonstrating that SPATE can act as immunomodulators at various levels of the immune system. SIGNIFICANCEWe have demonstrated for the first time that serine proteases (C2S) from clinically relevant pathogens, such as E. coli pathotypes and Shigella, can cleave leukocyte glycoproteins, including the tyrosine phosphatase CD45, which play crucial roles in cellular and immune functions. In this study, we discovered that C2S induces apoptosis in activated T cells through a previously unknown mechanism resembling IL-2 deprivation, mediated by CD45. Furthermore, we found that C2S is essential for bacterial virulence in vivo. This suggests that pathogens producing C2S may possess previously undescribed immunoregulatory functions that enhance their survival in the host and contribute to the disease process by eliminating T cells through the targeting of CD45 and the IL-2 receptor.

microbiology↗

bioRxiv2025

Discovery of a VHL molecular glue degrader of GEMIN3 by Picowell RNA-seq

Targeted protein degradation (TPD) is an emerging therapeutic modality in which small molecules are used to recruit targets to the natural protein degradation machinery of the cell. Molecular glue degraders (MGD) are monovalent small molecules that accomplish this by redirecting E3 ubiquitin ligases to target proteins, offering the potential to degrade previously unliganded and "undruggable" proteins in cancer, neurodegenerative, and other diseases. While attractive due to their drug-like properties, MGDs are exceptionally hard to discover and have largely been identified serendipitously. The Von Hippel-Lindau (VHL) E3 ligase is the second most widely used effector for TPD, though current VHL-based degraders are primarily large heterobifunctional PROTACs (proteolysis-targeting chimeras) designed using target-based ligands. Here, we have instead pursued target-agnostic discovery of VHL MGDs leveraging proprietary ultra-miniaturized microfluidics devices (Picowells) to facilitate unbiased RNA-seq screening of a biased E3-focused library. This resulted in dGEM3, a novel VHL molecular glue that targets the survival of motor neuron (SMN) complex member GEMIN3 for degradation. Through a combination of cellular, biochemical, and biophysical assays, we have characterized the GEMIN3 degron within its helicase ATP-binding domain, and how the kinetics of ternary complex formation impact degradation. These findings provide insights on the re-programmability of VHL for novel targets using drug-like molecular glues.

biochemistry↗

bioRxiv2025

Leveraging mRNA platform for the development of vaccines against egg allergy

Food allergy has posed a major global health burden due to the rising prevalence and lack of effective prophylactic strategies. During the past decades, allergen-specific immunotherapy (AIT) has been used as a disease-modifying therapy for food allergic conditions, but due to the long-term treatment duration, poor patient compliance and unexpected adverse reactions, only a minority of patients benefit from AIT therapy. In this proof-of-concept study, using well-established mRNA platform, we developed mRNA vaccine candidates encoding for the major egg white allergen Gal d2 (also known as ovalbumin) and comprehensively evaluated the prophylactic efficacy against anaphylaxis in a Gal d2-induced allergic mouse model. Two vaccine formulations, Gal d2 mRNA vaccine and Gal d2-IL-10 mRNA vaccine, both demonstrated effective ability in preventing the onset of allergic disease, which is largely attributed to the versatilities of mRNA vaccine in eliciting allergen-blocking antibody, shifting Th2 towards Th1 immunity, as well as in generating peripheral tolerance.

immunology↗

bioRxiv2025

MAIS: an in-vitro sandbox enables adaptive neuromodulation via scalable neural interfaces

Brain-machine interfaces (BMIs) predominantly rely on static digital architectures to decode biological neuronal networks, a paradigm that is incompatible with natural neural coding in the human brain1-4. Bridging this gap is a critical step in combating neuronal dysfunction, enhancing brain functionality, and refining the precision of neuroprosthetics5. The integration of brain organoids with microelectrode array (MEA), as a class of BMIs, offers a humanized in vitro platform with unique biological compatibility advantages for dynamic neuronal decoding. This study resolves the biological-electronic encoding incompatibility of brain organoid-MEA Integration through three progressive breakthroughs. First, a human-machine hybrid agent is developed as a newly proposed bioengineered platform that couples brain organoids together with high-density MEAs and computational chips, enabling closed-loop perturbation of biological neuronal networks via exogenous signals. Second, through plasticity-driven real-time tracking of neuronal activity, we establish dynamically reconfigurable stimulation nodes that self-align with the electrophysiological states of the organoids. This resolves the exogenous-endogenous encoding mismatch by implementing plasticity-driven adaptation principles that ensure biological compatibility through spatially adaptive coordination. Finally, through shared plasticity rules rather than centralized control, we construct the first scalable multi-agent interactive system (MAIS) and demonstrate its real-world applications. Through designed scenarios of pathological/normal neuronal network interaction, we validate that MAIS achieves stable cross-network coordination. MAIS embodies a self-evolving neural coding sandbox in which plasticity-driven dynamic decoding bridges the compatibility gaps between biological and digital systems, providing a scalable and foundational infrastructure for human-centered neural interfaces.

bioengineering↗

bioRxiv2025

Rewiring of 3D chromatin topology orchestrates transcriptional reprogramming in muscle fiber-type specification and transformation

The composition of muscle fibers, characterized by distinct contractile and metabolic properties, significantly influences meat quality and glucose homeostasis. However, the mechanisms by which three-dimensional (3D) genome topology integrates with epigenetic states to regulate muscle fiber specification and transformation remain poorly understood. Here, we present an integrative analysis of the transcriptome, epigenome, and 3D genome architecture in the slow-twitch glycolytic extensor digitorum longus (EDL) and fast-twitch oxidative soleus (SOL) muscles. Global remodeling of enhancer-promoter (E-P) interactions emerged as a central driver of transcriptional reprogramming associated with muscle contraction and glucose metabolism. We identified tissue-specific super-enhancers (SEs) that regulate muscle fiber-type specification through cooperation of chromatin looping and transcription factors such as KLF5. Notably, the SE-driven activation of STARD7 facilitated the transformation of glycolytic fibers into oxidative fibers by mitigating reactive oxygen species levels and suppressing ERK MAPK signaling. This study elucidates the principles of 3D genome organization in the epigenetic regulation of muscle fiber specification and transformation, providing a foundation for novel therapeutic strategies targeting metabolic disorders and enhancing meat quality. O_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC="FIGDIR/small/643571v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@990eecorg.highwire.dtl.DTLVardef@a2b491org.highwire.dtl.DTLVardef@1fcd142org.highwire.dtl.DTLVardef@10e4d47_HPS_FORMAT_FIGEXP M_FIG Schematic overview of the study. C_FIG

developmental biology↗

bioRxiv2025

AGP-Net: A Universal Network for Gene Expression Prediction of Spatial Transcriptomics

In the era of high-throughput biology, molecular phenotypes have proven effective in predicting disease states and future trajectories. Transcriptomics, in particular, has enabled the dissection of complex diseases with heterogeneous genetic and environmental aetiology, both aiding diagnosis and augmenting treatment. As improving technology has led to measurements of gene expression at increasing granularity, it has become progressively feasible to resolve disease traits that present locally or with spatial heterogeneity. Principal among these are cancers in which tumour gene expression, while itself heterogenous, exhibits a distinct signature from that of the surrounding tissue. Identifying this signature through molecular phenotyping facilitates specific cancer diagnosis and treatment. Here, we introduce AGP-Net, a multi-modal foundation framework capable of predicting gene expression from histopathology images. Rather than produce an aggregated estimate of expression for each gene, AGP-Net disaggregates images into spots and attempts to resolve the variation in gene expression across them, thereby providing coarse spatial transcriptomic predictions across the tumour slice and surrounding region. The challenge in doing so is due to data sparsity relative to the dimensionality of the problem: the number of genes and their contextual heterogeneity within and between tissue and cancer types makes it difficult to train a model on the limited data available. The innovation of AGP-Net lies in borrowing strength across similar genes as defined by their textual language descriptions. Our AGP-Net supports datasets with varying gene coverage and facilitates the prediction of gene expression for previously unseen genes based on their textual descriptions. Trained on millions of spots from diverse dataset sources, AGP-Net establishes state-of-the-art performance in zero-shot spatial gene expression prediction, demonstrating its adaptability to generalize across novel scenarios.

pathology↗

bioRxiv2025

The Neurocognitive Mechanisms Underlying Narrative Schematic and Paraphrastic Transmission

Narrative transmission serves multiple crucial functions, such as cultural preservation, knowledge accumulation, and consensus building, in human society. However, our understanding of its neurocognitive mechanisms remains limited. In this study, we combined a social transmission chain design with fMRI to investigate the dynamic changes of different narrative components occurring throughout transmission chains and to uncover the factors driving fidelity and distortion. A total of 58 participants were scanned as they listened to and subsequently recalled a story within a social transmission chain. We distinguished two types of transmission modes: schematic transmission, which prioritizes preserving the structural framework of the information, and paraphrastic transmission, which entails rephrasing the content while conveying its meaning. Behavioral results revealed a pattern in which paraphrastic transmission led to distortion and divergence, whereas schematic transmission remained more stable and convergent. Neural findings indicated that the transmission of story structure and content involved subsystems of the Default Mode Network (DMN) and specific subregions of the Hippocampus (HPC). While neural reinstatement between narrative listening and speaking failed to predict across-generation fidelity of content and structure, functional connectivity pattern similarity analysis showed that the DMN and HPC work as an episodic memory system supporting transmission performance. These findings highlight that narrative transmission is supported by distinct neurocognitive representations within episodic memory subsystems, which work collaboratively to sustain the transmission of narratives.

neuroscience↗

bioRxiv2025

Improved Prediction of Bacterial Type VI Secretion Effector Proteins Using an Integrated Convolutional Neural Network Model Combining N-terminal Signal Sequences, Evolutionary Information and Pre-Trained Protein Language Features

Type VI secretion system effectors (T6SEs) are crucial for bacterial pathogenicity, making their accurate identification essential for understanding bacterial virulence mechanisms. This study analyzed the differences in amino acid composition of N-terminal signal sequences between T6SEs and non-T6SEs, uncovering distinct positional amino acid preferences in T6SEs. Using a combination of unsupervised and supervised analysis, we evaluated feature encoding methods and developed T6CNN, an ensemble model that integrates N-terminal signal sequences, evolutionary information, and pre-trained protein language features for T6SE prediction. T6CNN demonstrated outstanding performance in independent testing, outperforming existing tools with a 7.9% accuracy increase (to 0.953), a 13.2% sensitivity improvement (to 0.964), and a 6.6% specificity enhancement (to 0.951). The T6CNN model offers a reliable and accurate solution for T6SE prediction, with significant potential to advance research on bacterial pathogenicity. ImportanceThis study introduces T6CNN, a new computational model for identifying Type VI secretion system effectors used by harmful bacteria. By analyzing early protein sequences, T6CNN uncovers unique features that reliably distinguish effector proteins. Integrating evolutionary data and pre-trained protein language features, the model outperforms existing methods in accuracy, sensitivity, and specificity. This enhanced prediction tool deepens our understanding of bacterial infection mechanisms and offers researchers a valuable resource for pinpointing key virulence factors. Ultimately, T6CNN may help drive the development of more targeted antibacterial treatments and strategies to combat bacterial diseases.

bioinformatics↗

bioRxiv2025

Oxytocin receptor and HER2 interactions in breast cancer

Breast cancer affects women globally, with HER2 being one of the most aggressive subtypes. Despite advances in HER2-targeted therapies, many patients fail to respond to such treatments. In search of alternative therapeutic targets, we investigated the role of the oxytocin (OT) and oxytocin receptor (OTR) signalling system in HER2+ breast cancer. Survival analysis of HER2 subtype breast cancer patients revealed high OTR expression correlating with significantly improved relapse-free survival. OTR overexpression or knockdown in HER2+ SK-BR-3 cells decreased or increased cell viability, respectively. HER2 was downregulated in OTR-overexpressing cells, which could contribute to the decreased Pertuzumab efficacy. Importantly, HER2 was internalised upon OT treatment and interacted with OTR to form OTR-HER2 complexes. OT treatment furthermore induced a transient inhibition of HER2 phosphorylation without affecting the total HER2 protein levels. In addition, OT inhibited ERK1/2 phosphorylation but enhanced Akt phosphorylation, linked to increased cell viability. In summary, this work describes a novel HER2-OTR interaction and mechanism, expanding our understanding of HER2 cancer biology that might lead to new prognostic and therapeutic opportunities centred around the OT/OTR signalling system for patients suffering from HER2+ breast cancer.

cancer biology↗

bioRxiv2025

Tumor hypoxia adaptation depends on FLAD1 mediated mitochondrial metabolic reprogramming

Hypoxia, a hallmark of solid tumors, promotes the malignant progression and is challenging to target. Metabolic reprogramming and the resulting metabolic vulnerabilities provide a promising strategy to target tumor hypoxia. Here we systematically compared the metabolic network differences between hypoxic and non-hypoxic cells, and developed a deep learning model, "DepFormer", to predict the dependent metabolic genes in hypoxic tumor cells. The performance of DepFormer was validated using CRISPR screening dataset. Oxidative phosphorylation was identified as the most significantly hypoxia-dependent metabolic pathway, and FLAD1 was predicted to be one of the key hypoxia-dependent metabolic genes. FLAD1 locus is amplified, and FLAD1 expression is upregulated in various tumor types, especially in hypoxic tumors. FLAD1 depletion compromises tumors adaptation to hypoxia by disrupting mitochondrial complex II activity, leading to an imbalance between succinate and fumarate, and consequent failure to adapt to hypoxia. Subsequently, we identified a drug-like inhibitor of FLAD1, which selectively inhibits the growth of tumor cells under hypoxia. Our findings reveal FLAD1 as an innovative therapeutic target for hypoxic tumors.

cancer biology↗

bioRxiv2025

Exogenous melatonin mitigates drought stress by promoting the living cortical area of roots in cotton

The root cortex plays a critical role in water absorption, influencing root function and metabolic activity. However, the effects of melatonin on root cortical cells and its role in drought resistance remain unclear. This study examines the impact of exogenous melatonin on the root cortex of cotton under drought stress, focusing on its relationship with water uptake and drought resilience. Cotton plants were treated with 8% PEG6000 for drought stress and 100 {micro}M melatonin by foliar application. The results demonstrated that melatonin application significantly increased the living cortical area of roots under drought stress, with notable increases of 26.34% and 59.00% at distances of 1 cm and 13 cm from the root tip, respectively. Melatonin also enhanced root cortical thickness, promoted osmotic regulation, increased respiratory enzyme activity, and improved water and nutrient uptake. Furthermore, melatonin application promoted both root and shoot growth. Notably, the living cortical area positively correlated with osmotic substance accumulation, root respiration, and absorption capacity under drought conditions. In conclusion, exogenous melatonin alleviates drought-induced damage by enhancing the living cortical area, optimizing osmotic regulation, and improving root absorption, thus promoting cotton growth and drought resistance. These findings highlight melatonin as a promising regulator for enhancing drought resistance. HighlightExogenous melatonin increases root cortical integrity of cotton roots under drought stress, improves the absorption of water and nutrients, promotes the growth of cotton, and enhances its drought resistance.

physiology↗

bioRxiv2025

Lymph nodes link sex-biased immune aging to compromised antigen recognition

The numerical abundance of diverse naive CD8 T cell clones is essential to provide broad protection against infection and cancer. Here, we uncover a sex-biased mechanism of immune aging in which an early, male-biased depletion of naive CD8 T cells driven by accelerated, antigen-agnostic differentiation into virtual memory cells is combined with age-related thymic involution that limits naive CD8 T cell replenishment. These mechanisms lead to contraction of lymph nodes and reduced local naive T cell clone availability, limiting cancer antigen recognition capacity. Therapeutic thymus regeneration via androgen ablation repopulates naive CD8 T cells in lymph nodes, which reinvigorates cancer-specific T cell responses and enhances responsiveness to immune checkpoint blockade. These findings reveal the crucial impact of sex and age on naive T cell clone abundance in lymph nodes and suggest strategies to restore immune competence in middle-aged males.

immunology↗