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Zheng, X.

Publications and source records attributed to Zheng, X..

At least 91 records · Page 5Linked to original sources
bioRxiv2025

Sky islands of Southwest China. II: Unraveling hidden species diversity of talpid moles using phylogenomics and skull-based deep learning

The sky islands of Southwest China, characterized by dramatic topographical and climatic variations, are prominent hotspots of biodiversity and endemism. Organisms inhabiting middle-to-high elevation habitats in this region are geographically isolated within distinct mountain chains, which over geological time have been subjected to isolation-by-distance and isolation-by-environment. These processes have led to profound allopatric diversification and strong phylogeographic structuring, resulting in a plethora of genetically distinct cryptic species, as is becoming increasingly evident for many small mammal families. However, morphological conservatism can pose significant challenges in delineating these clades within species complexes. In this study, we leverage artificial intelligence technologies to unravel the hidden species diversity of moles (family Talpidae) in Southwest Chinas sky islands. We first employed ultraconserved elements (UCEs) to investigate the evolutionary history of talpid moles, conducted molecular species delimitation using mitochondrial and multi-locus genes, and utilized both traditional and geometric morphometrics to examine their morphological disparity. To address the challenges of morphology based cryptic species identification, we developed a deep learning Hierarchical Identification of Species NETwork (HIS-NET) to create an image-based model that analyzes four different views of the skull/mandible to distinguish genera and species hierarchically. HIS-NET not only achieved expert-level accuracy in species identification but also effectively distinguished between cryptic and known species, aiding in the identification of key morphological variation intervals. Our results support the recognition of allopatrically distributed taxa in Euroscaptor and Parascaptor as full species, thereby confirming that species diversity in this region remains underestimated. Beyond advancing our understanding of speciation in this unique and fragile ecosystem, our study serves as a proof-of-concept, demonstrating the power of deep learning in unraveling hidden biodiversity within this and other species complexes.

zoology↗
bioRxiv2025

A functional anatomical shift from the lateral frontal pole to dorsolateral prefrontal cortex in emotion action control underpins elevated levels of anxiety: partial replication and generalization of Bramson et al., 2023

Flexible control over emotional behavior represents a promising target for novel interventions for mental disorders. Accumulating evidence has indicated a key role of the lateral frontal pole (FPl) and its connections with other cortical and subcortical systems in emotional action regulation. A recent study from Bramson et al., (2023) employed a multi-modal neuroimaging approach to demonstrate a functional-anatomical shift from FPI to dorsolateral prefrontal cortex (DLPFC) in a sample of anxious individuals during emotional action control. While these findings might represent a venue for interventions in anxiety disorders, conventional neuroimaging strategies are often limited with respect to generalizability and reproducibility. Against this background we capitalized previous large-scale fMRI data in n = 250 participants using an affective linguistic Go/NoGo paradigm to examine the robustness of the reported associations with trait social anxiety across samples, cultures and paradigms. Additionally, context-dependent functional connectivity patterns were explored to examine action control in different emotional contexts. In line with previous study, we found no difference between high- and non-anxious group on the behavioral congruency-effect. The neural results showed that non-social anxious group engaged the left FPl while the high-social anxious group specifically recruited the DLPFC, however in the absence of significant between-group differences. Importantly, the level of trait social anxiety was significantly positively related with DLPFC activity and negatively with left FPl activation across groups. Furthermore, context-dependent functional connectivity analyses revealed a negative context-specific neural shift from the sgACC-FPl to sgACC-DLPFC specifically in the high anxiety group. Together, the present study employed a different task paradigm, population and analytic methods, partially replicated the findings described by Bramson et al., (2023) and additionally determined context-specific changes in the communication with the sgACC in high anxiety. The findings provide further evidence for target-based interventions of persistent emotional control deficits in anxiety disorders.

neuroscience↗
bioRxiv2025

Proximity determines donor candidacy during DNA double-stranded break homology directed repair

DNA double-stranded breaks (DSBs) are especially toxic events that can be reversed by homology-directed repair (HDR), wherein information is copied from an intact template molecule. RAD51 mediates initial DSB/template pairing during homology search. A major challenge in understanding homology search in cells is the lack of tools to monitor this process. We developed RAD51 proximity identification sequencing (RaPID-seq), a sensitive method that marks all candidate templates searched by RAD51. We find that HDR is hierarchical, such that DSB proximity determines template candidacy and subsequent recombination is unlocked by DSB/template homology. Sequences that lie outside the proximal window are not efficiently searched, even if identical in sequence. Our data reveal the invisible process of homology search and shed new light on fundamental mechanisms underlying genome editing.

molecular biology↗
bioRxiv2025

Avoidance of fratricide and improved efficacy of CD33-MSLN CAR-iNK cells in treating acute myeloid leukemia

Acute myeloid leukemia (AML) patients are often older, which brings challenges of endurance and persistent efficacy of autologous CAR-T cell therapies. Allogenic CAR-NK cell therapies may offer reduced toxicities and enhanced anti-leukemic potential against AML. In this study, we designed a novel CD33-mesothelin loop CAR (Loop CAR) and evaluated its anti-tumor efficacy in human umbilical cord blood-derived NK (UCB-NK) cells and human pluripotent stem cell-derived NK (hPSC-iNK) cells. The Loop CAR exhibited superior cytotoxicity against dual-antigen-positive tumor cell lines and primary AML cells. To further avoid fratricide caused by endogenous CD33 expression in NK cells, we established a hPSC-derived cell line via knockout of CD33 gene (CD33KO) and engineered Loop CAR. Rather than enforced expression of exogenous CD16, we generated abundant mature CD33KO-Loop CAR-iNK cells highly expressing endogenous CD16 via an organoid induction approach. This innovative strategy effectively mitigated NK cell fratricide and significantly enhanced CD33 and mesothelin-mediated specific cytotoxicity. Moreover, the CD33KO-Loop CAR-iNK cells demonstrated superior tumor-killing activity in AML xenograft mice and significantly prolonged survival. hPSC-derived CD33KO-Loop CAR-iNK cells possess unique advantages and translational potential for treating AML.

cancer biology↗
bioRxiv2025

Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies

BackgroundT cell malignancies are highly aggressive hematological tumors with limited effective treatment options. CAR-NK cell therapy targeting CD7 has emerged as a promising approach for treating T-cell malignancies. However, conventional CAR-NK cell therapy faces the challenges of cell fratricide due to CD7 expression on both malignant cells and normal NK cells. Additionally, engineering CARs into human tissue-derived NK cells demonstrates heterogeneity, low transduction efficiency, and high manufacturing costs. MethodsThe human pluripotent stem cells (hPSCs) were genetically modified by knocking out the CD7 gene and introducing the CD7 CAR expression cassette to generate CD7 KO-CD7 CAR-hPSCs. These modified hPSCs were subsequently differentiated into CD7 KO-CD7 CAR-iNK cells using an efficient organoid induction method. The cytotoxicity of CD7 KO-CD7 CAR-iNK cells against CD7+ tumor cells was evaluated. Furthermore, we overexpressed the CXCR4 gene in CD7 KO-CD7 CAR-hPSCs and derived CXCR4-expressing CD7 KO-CD7 CAR-iNK (CRO-CD7 CAR-iNK) cells. The dynamics of CRO-CD7 CAR-iNK cells in vivo were tracked, and their therapeutic efficacy was assessed using human T-cell acute lymphoblastic leukemia (T-ALL) xenograft models. ResultsThe CD7 KO-CD7 CAR-iNK cells derived from CD7 KO-CD7 CAR-hPSCs effectively avoided fratricide, demonstrated normal expansion, and exhibited potent and specific anti-tumor activity against CD7+ T-cell tumor cell lines and primary T-ALL cells. CXCR4 overexpression in CRO-CD7 CAR-iNK cells improved their homing capacity and extended their persistence in vivo. The CRO-CD7 CAR iNK cells significantly suppressed tumor growth and prolonged the survival of T-ALL tumor-bearing mice. ConclusionsOur study provides a reliable strategy for the large-scale generation of fratricide-resistant CD7 CAR-iNK cells with robust anti-tumor effects from hPSCs, offering a promising cell product to treat T-cell malignancy.

cancer biology↗
bioRxiv2025

ca-circSCN8A promotes HPASMCs ferroptosis via LLPS initiated R-Loop

BACKGROUNDFerroptosis has been implicated in pulmonary hypertension. Chromatin-associated RNAs are linked to ferroptosis. However, their role in pulmonary vascular ferroptosis in PH is unexplored. METHODSBioinformatics, Sanger sequencing, RNase R and others were employed to identify differentially higher expression of ca-circSCN8A. Functional gain and loss assays were employed to unveil the role of ca-circSCN8A in hypoxia-induced redox-dependent ferroptosis in HPASMCs and PH mice model. Interaction between ca-circSCN8A and FUS was detected via RNA immunoprecipitation and pull-down assays. FRAP, CHIRP-qPCR, MDA, GSH and GSSG were conducted to explore the potential molecular mechanism. RESULTSca-circSCN8A was firstly identified and confirmed to be upregulated in PH. Upregulation of ca-circSCN8A can promote hypoxia induced ferroptosis in HPASMCs. Under hypoxic conditions, ca-circSCN8A promoted the lactylation of FUS by recruiting EP300, leading to formation of LLPS of ca-circSCN8A/FUS/EP300. LLPS maintained the stability of the R-Loop formed by ca-circSCN8A and ferroptosis related-gene SLC7A11 promoter that inhibit the transcription of the SLC7A11 gene, further result in the disruption of the redox balance and causes ferroptosis in HPASMCs. CONCLUSIONSca-circSCN8A recruits EP300 to promote the lactylation of FUS, thereby promoting LLPS formation of ca-circSCN8A/EP300/FUS. Further, the LLPS motivates ca-circSCN8A to form R-loop with its non-host SLC7A11 and participating in the regulation of hypoxic induced HPASMCs redox-dependent ferroptosis. This is the first confirmation that circRNAs forming R-loops with non-host genes regulated by LLPS. Our findings indicated that ca-circSCN8A plays an important role in ferroptosis of hypoxic induced HPASMCs and may be a potential target for the treatment of PH.

molecular biology↗
bioRxiv2025

Cholinergic dynamics in the septo-hippocampal system provide phasic multiplexed signals for spatial novelty and correlate with behavioral states

In the hippocampal formation, cholinergic modulation from the medial septum/diagonal band of Broca (MSDB) is known to correlate with the speed of an animals movements at sub-second timescales and also supports spatial memory formation. Yet, the extent to which sub-second cholinergic dynamics, if at all, align with transient behavioral and cognitive states supporting the encoding of novel spatial information remains unknown. In this study, we used fiber photometry to record the temporal dynamics in the population activity of septo-hippocampal cholinergic neurons at sub-second resolution during a hippocampus-dependent object location memory task using ChAT-Cre mice. Using a general linear model, we quantified the extent to which cholinergic dynamics were explained by changes in movement speed, behavioral states such as locomotion, grooming, and rearing, and hippocampus-dependent cognitive states such as recognizing a novel location of a familiar object. The data show that cholinergic dynamics contain a multiplexed code of fast and slow signals i) coding for the logarithm of movement speed at sub-second timescales, ii) providing a phasic spatial novelty signal during the brief periods of exploring a novel object location, and iii) coding for environmental novelty at a seconds-long timescale. Furthermore, behavioral event-related phasic cholinergic activity around the onset and offset of the behavior demonstrates that fast cholinergic transients help facilitate a switch in cognitive and behavioral state before and during the onset of behavior. These findings enhance understanding of the mechanisms by which cholinergic modulation contributes to the coding of movement speed and encoding of novel spatial information.

animal behavior and cognition↗
bioRxiv2025

Single cell resolved spatial immune repertoire unveils spatial heterogeneity of lymphoid aggregates in human immune disorders

Adaptive immunity, mediated by T and B cell responses, is essential for defending against infections and cancers while also being implicated in autoimmune diseases. Tracking T and B cell repertoires in situ at single-cell resolution is essential for understanding adaptive immune responses. To address the lack of tools for in situ single-cell T/BCR (XCR) sequencing, we developed Stereo-XCR-seq, an efficient strategy for retrieving and sequencing TCR and BCR from Stereo-seq cDNA libraries at subcellular resolution. Stereo-XCR-seq provides unbiased full-length XCR reads alongside spatial transcriptomics, enabling the identification of heterogeneous lymphoid aggregates with distinct clonal activities in cancers and inflammatory bowel disease (IBD). We identified plasma cell aggregates that differ from tertiary lymphoid structures (TLSs) in both transcriptomic profiles and clonal activities, with spatial positioning potentially mediating unique immune responses. Collectively, Stereo-XCR-seq enables in situ single-cell profiling of T and B cell clonal activities within tissue microenvironments, providing insights into lymphocyte adaption to environmental stimuli. This technology provides potential for advancing our understanding of tissue immunity and the development of therapeutic strategies for immune disorders.

immunology↗
bioRxiv2025

A multilamellar organelle for chemosymbiosis in an aplacophoran mollusc adapted to anoxic cold seep sediment

Symbiosis with chemoautotrophic bacteria has evolved in many animal lineages inhabiting reducing habitats such as hydrothermal vents, allowing these holobionts to thrive in dark biospheres1. In certain instances, the symbionts have become intracellular, residing within specialised bacteriocytes2. The integration of microbial symbionts with eukaryotic cells vary across known animals; however, no specialised organelle dedicated to chemosynthesis has been identified yet2. Here, we report a mode of symbiosis where sulphur-oxidising bacteria cultured within spherical multilamellar compartments (~12 m) in the cold-seep aplacophoran mollusc Chaetoderma shenloong. This organelle, which we name dracosphera, is ubiquitous within the hypertrophied and intricately reticulate digestive gland of C. shenloong, which has otherwise lost most of its gut. Given that the symbionts are strictly anaerobic and the host resides in anoxic sediments tens of centimetres below the surface, the dracosphera may serve to minimise oxygen diffusion to the bacteria, akin to mechanisms observed in microbial diazotrophs3 or termite hindguts4, as supported by our genomic and spatial transcriptomic analyses. Hypoxic conditions have been known to induce radical adaptations in meiofauna, exemplified by the acquisition of hydrogenosomes5. Our discovery of similarly exceptional adaptations in C. shenloong provides new insights into the evolution of such organelles also in larger animals.

microbiology↗
bioRxiv2025

Ustilaginoidea virens suppresses floral immunity through promoting GA biosynthesis by the effector SCRE9

Rice false smut caused by Ustilaginoidea virens has become one of the most important rice diseases. U. virens specifically infects rice florets through stamen filaments. However, it is mysterious how U. virens inhibits floral immunity for successful colonization. Here, we show that a small cysteine-rich effector SCRE9 is a key virulence factor in U. virens. Expression of SCRE9 in rice not only suppresses immune responses and false smut resistance, but also significantly increases expression of expansin and gibberellin (GA) biosynthetic genes and GA content in young rice panicles. We further demonstrate that OsSIP1 (SCRE9-interacting protein 1) in rice is targeted by SCRE9 and interacts with the OsMADS63 and OsMADS68 transcription factors that transcriptionally regulate the GA synthesis gene GA3ox1. Interestingly, the chloroplast-localized OsSIP1 recruits OsMADS63/68 into the chloroplast. SCRE9 causes OsSIP1 to be translocated into the nucleus, thereby releasing OsMADS63/68 from the chloroplast into the nucleus to promote GA3ox1 transcription. Therefore, SCRE9 promotes GA biosynthesis and expression of expansins in rice florets, thus loosening cell walls and overcoming the physical barrier during U. virens infection. The finding uncovers an unidentified floret infection strategy that offsets the deficiency in cell wall degrading ability in the unique floret colonizing fungus.

plant biology↗
bioRxiv2024

Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants; however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs. Here, we leverage a new scalable wet-lab protocol and computational pipeline for whole-genome Oxford Nanopore Technologies sequencing and apply it to neurologically normal control samples from the North American Brain Expression Consortium (NABEC) (European ancestry) and Human Brain Collection Core (HBCC) (African or African admixed ancestry) cohorts. Through this work, we present a publicly available long-read resource from 351 human brain samples (median N50: 27 Kbp and at an average depth of ~40x genome coverage). We discover approximately 234,905 SVs and produce locally phased assemblies that cover 95% of all protein-coding genes in GRCh38. To resolve cis-regulatory effects, we develop ASM-LR, a method for allele-specific methylation analysis from long-read data, revealing both strong and subtle regulatory effects, including numerous novel methylation QTLs masked in unphased models. Our results highlight the power of haplotype-resolved methylation to uncover regulatory mechanisms and establish a foundational resource for exploring how genetic variation shapes gene expression and epigenetic architecture across diverse ancestries.

genomics↗
bioRxiv2024

Patient-Derived Xenografts of Triple-Negative Breast Cancer Enable Deconvolution and Prediction of Chemotherapy Responses

Chemotherapy regimens for triple-negative breast cancer (TNBC) combine agents without knowing which agents drive response. Consequently, predictors derived from multi-agent regimens cannot be assumed to generalize to individual drugs or other regimens, motivating development of treatment-matched predictors. Here, we used TNBC patient-derived xenografts (PDXs) treated with carboplatin, docetaxel, or the combination to deconvolute drug-specific responses and identify associated molecular features. Combination treatment rarely improved upon the best single agent, with enhanced responses in only 13% of PDXs and antagonism in a comparable fraction. Proteogenomic analyses identified high cytokeratin-5 (KRT5) as a general marker of chemotherapy responsiveness and KRT5 immunohistochemistry discriminated responsive PDXs (AUROC, 0.83). To train treatment-specific predictors, we integrated these data with independent PDX and clinical cohorts with responses assessed after anthracycline-free platinum, taxane, or platinum-taxane therapy, ensuring response corresponded to the modeled treatment. Four feature selection strategies yielded largely nonoverlapping biomarker panels converging on treatment-relevant pathways. On independent test data, RNA-based predictors of complete response (CR) to platinum-based (carboplatin or cisplatin) and taxane-based (docetaxel or paclitaxel) chemotherapy achieved AUROCs of 0.80 and 0.86, respectively. For platinum-taxane regimens (carboplatin plus docetaxel or paclitaxel), proteomic-guided feature selection generated a 10-biomarker, protein- informed RNA predictor of pathologic complete response (pCR) that outperformed RNA-only feature selection and achieved an AUROC of 0.85 in an independent clinical cohort, while retaining practicality as an RNA-based assay. Treatment-matched integration of multi-omic PDX and clinical datasets provides a framework for chemotherapy-specific predictors with clinically relevant performance, supporting biomarker-guided precision selection and treatment optimization for patients with TNBC. Statement of significanceIntegration of multi-omic data from patient-derived xenografts with treatment-matched clinical cohorts yielded three retrospectively validated predictors of platinum, taxane, and platinum+taxane response, enabling biomarker-guided chemotherapy selection for patients with triple-negative breast cancer.

cancer biology↗
bioRxiv2024

Cervicovaginal microbial features predicts Chlamydia trachomatis spread to the upper genital tract of infected women

IntroductionChlamydia trachomatis (CT) infection can lead to pelvic inflammatory disease, infertility and other reproductive sequelae when it ascends to the upper genital tract. Factors including chlamydial burden, co-infection with other sexually-transmitted bacterial pathogens and oral contraceptive use influence risk for upper genital tract spread. Cervicovaginal microbiome composition influences CT susceptibility and we investigated if it contributes to spread by analyzing amplicon sequence variants (ASVs) derived from the V4 region of 16S rRNA genes in vaginal samples collected from women at high risk for CT infection and for whom endometrial infection had been determined. ResultsParticipants were classified as CT negative (CT-, n=77), CT positive at the cervix (Endo-, n=77), or CT positive at both cervix and endometrium (Endo+, n=66). Although we were unable to identify many significant differences between CT infected and uninfected women, differences in abundance of ASVs representing Lactobacillus iners and L. crispatus subspecies but not dominant lactobacilli were detected. Twelve informative ASVs predicted endometrial chlamydial infection (AUC=0.74), with CT ASV abundance emerging as a key predictor. We also observed a positive correlation between levels of cervically secreted cytokines previously associated with CT ascension and abundance of the informative ASVs. ConclusionOur findings suggest that vaginal microbial community members may influence chlamydial spread directly by nutrient limitation and/or disrupting endocervical epithelial integrity and indirectly by modulating pro-inflammatory signaling and/or homeostasis of adaptive immunity. Further investigation of these predictive microbial factors may lead to cervicovaginal microbiome biomarkers useful for identifying women at increased risk for disease.

microbiology↗
bioRxiv2024

CellPatch: a Highly Efficient Foundation Model for Single-Cell Transcriptomics with Heuristic Patching

The rapid advancement of foundation models has significantly enhanced the analysis of single-cell omics data, enabling researchers to gain deeper insights into the complex interactions between cells and genes across diverse tissues. However, existing foundation models often exhibit excessive complexity, hindering their practical utility for downstream tasks. Here, we present CellPatch, a lightweight foundation model that leverages the strengths of the cross-attention mechanism and patch tokenization to reduce model complexity while extracting efficient biological representations. Comprehensive evaluations conducted on single-cell RNA-sequencing datasets across multiple organs and tissue states demonstrate that CellPatch achieves state-of-the-art performance in downstream analytical tasks while maintaining ultra-low computational costs during both pretraining and finetuning phases. Moreover, the flexibility and scalability of CellPatch allow it to serve as a general framework that can be incorporated with other well established single-cell analysis software, thereby enhancing their performance through transfer learning on diverse downstream tasks.

bioinformatics↗
bioRxiv2024

A regulator controls both DNA damage response and anti-phage defense networks in Moraxellaceae

DNA damage chemicals, including many antibiotics, often induce prophage induction and phage outbreaks in microbial communities, a major threat to bacterial survival. Moraxellaceae contains clinically highly relevant strains with outstanding antibiotic and radio resistance, yet their cellular-level regulation in DNA damage response and anti-phage defense is largely unknown. Here, we identified a WYL family protein that had replaced the ubiquitous SOS system in evolution and directly regulated a transcriptional network of both DNA repair genes and anti-phage defense genes under DNA damage stress. This study depicts a mechanism that how bacteria maintain immunity to phages without compromising on antibiotic resistance, and sheds light on controlling the resistance of Moraxellaceae strains in clinical practice.

microbiology↗
bioRxiv2024

Circular RNA AEBP2: A novel regulator in dendritic cell development

Dendritic cells (DCs) are the main antigen-presenting cells and play a central role in activating adaptive immunity. How DCs is regulated during their development remains to be further elucidated. Circular RNA (circRNA) is a new type of non-coding RNA playing a critical in various cell events. However, little is known about the role of circRNA in DCs. Using in situ RNA hybridization, we found that DCs expressed exonic circular RNA AEBP2 (circAEBP2). circAEBP2 was upregulated in mature DCs compared to immature DCs. Knockdown of circAEBP2 in DCs using small interference RNA (siRNA) arrested DCs at an immature state with lower expression of MHC class II, CD40, CD80, and CD83. circAEBP2 knockdown in DCs also decreased the phosphorylation of nuclear factor-kappa B p65 (P-p65) but increased CD200R1. CircAEBP2-silenced DCs had a lower capacity to activate allogeneic CD4+ and CD8+ T cells in vitro and induced differentiation of regulatory T cells (Tregs). RNA immunoprecipitation assays revealed that circAEBP2 interacts with heterogeneous nuclear ribonucleoprotein F (hnRNP F) which is highly expressed in DCs and subsequently prevented hnRNP F nuclear translocation. In conclusion, we demonstrate that circAEBP2 regulates the development and function of DCs and knockdown of circAEBP2 induces tolerogenic DCs (Tol-DCs) through interacting with the hnRNP F/CD200R1/P-p65 signaling pathway. circAEBP2 is a new regulator in DCs and modulating it provides a novel strategy for inducing Tol-DCs.

immunology↗
bioRxiv2024

Immunogenic shift of arginine metabolism triggers systemic metabolic and immunological reprogramming to prevent HER2+ breast cancer

Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing SEP, the endogenous precursor of BH4 (the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we report that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively prevented tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention. These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.

cancer biology↗