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Preprints

New results on bioRxiv and medRxiv, before peer review.

101 selectedRelated topicsOriginal researchMethods and resourcesSingle-cell and spatial omics

Latest picks

61–80 of 101
Sep 28Mon
  1. bioRxiv Cancer Biology67

    Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

    Disrupting the SWI/SNF chromatin remodeling complex in tumor-associated macrophages reprograms them and improves checkpoint blockade immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity slowed tumor growth, and deleting the SWI/SNF subunit Arid1a in myeloid cells was sufficient to suppress tumor progression and enhance checkpoint blockade response. The reprogramming involved reduced enhancer accessibility at poor-prognosis genes such as Spp1, increased accessibility at interferon-stimulated gene promoters, elevated CD86, and required CD86 costimulation and CD8+ T cells.

    Why it matters: It identifies a druggable epigenetic target in macrophages that improves checkpoint blockade response.

  2. bioRxiv Genomics54

    Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

    Mosaic structural variants occur in all individuals and germ layers, with long- and short-read WGS of 47 normal tissues (168 samples) showing a median 285.2 kb affected per genome. Most variants were repeat-mediated and 8.3% overlapped functional elements, enriched relative to germline variants. Repeat alterations measured from short reads across 15 cancer types matched normal mosaic variation in scale and enabled tumor tracking in cell-free DNA.

    Why it matters: Quantifies repeat-driven mosaic structural variation in normal tissues and shows repeat changes in cell-free DNA can monitor tumors.

  3. bioRxiv Cancer Biology62

    A meiotic B-type cyclin selectively drives mitotic progression and fidelity in cancer cells

    Cyclin B3, previously thought to act only in female meiosis, is expressed in mitotic cells and partners with CDK1 and CDK2 to drive timely mitotic progression through proper chromosome alignment and stable kinetochore-microtubule interactions. Depleting cyclin B3 disrupted mitosis in most cancer cell lines tested, including colorectal, osteosarcoma, and breast cancer models, while non-transformed cells were largely unaffected. Phospho-mass spectrometry identified kinetochore and mitotic spindle components as substrates, pointing to a preferential cancer-cell dependency.

    Why it matters: It identifies cyclin B3-CDK1/2 as a mitotic driver that cancer cells depend on more than non-transformed cells.

  4. bioRxiv Genomics62

    Structural polymorphism and population-variable coding capacity of HERV-K(HML-2) in human pangenomes

    Haplotype-resolved long-read assemblies from 292 donors reveal extensive structural polymorphism in HERV-K(HML-2) proviruses: tandem arrays at 13 loci with up to six copies each, a previously undescribed full-length provirus at 8q11.23, and intact open reading frames in many individuals where reference genomes carry disruptive mutations. Short-read genotyping left 32.5% of donor-variant pairs unresolved at sites tied to viral reading frames. HML-2 expression studies should account for the coding alleles each individual carries.

    Why it matters: Reference-based short-read methods miss HML-2 structural and coding variation that affects interpretation of HERV expression in disease.

  5. bioRxiv Cancer Biology56

    ctDNA Release Heterogeneity in Luminal Breast Cancer Revealed by Single-Cell Multi-Omics Spatial Analysis

    Eight recurrent malignant epithelial states in non-metastatic HR+/HER2- breast cancer show distinct ctDNA release potential, defined by scMASTER, a framework combining single-cell transcriptomes and mutations, spatial transcriptomics and matched tumor and plasma DNA sequencing across ten patients. Antigen-presentation, stress, mitosis and mesenchymal-like states released most ctDNA, as did EMT-enriched regions, intraductal luminal progenitors and avascular hypoxic zones. PIK3CA and ESR1 mutations tied to distinct functional states altered ctDNA detectability, and a stratification model from these features identified high-risk, immunosuppressed patients with poor prognosis in external cohorts.

    Why it matters: It explains cellular and spatial sources of tissue-plasma discordance that limit liquid biopsy in HR+/HER2- breast cancer.

  6. bioRxiv Cancer Biology54

    Integrated immunopeptidomics and transcriptomics reveal a cancer-restricted non-canonical HLA class I ligandome in medulloblastoma

    Non-canonical HLA class I peptides could widen the target pool for T-cell immunotherapy in medulloblastoma, a tumor with low mutational burden. Integrated immunopeptidomics and transcriptomics across 21 samples covering the four molecular subgroups identified 2,298 non-canonical HLA-I peptides, 598 of them cancer-restricted, derived mainly from retained introns, out-of-frame open reading frames, and long non-coding RNAs. More than 70% were predicted to bind a patient-matched HLA allotype and about 87% to be immunogenic.

    Why it matters: It expands the antigen repertoire available for T-cell therapy in a low-mutational-burden childhood brain tumor.

  7. bioRxiv Genomics57

    RNA isoform-resolved multiplexed sequencing with bioorthogonal barcoding

    Bobcodes, bioorthogonal barcodes attached at multiple internal positions along cellular RNAs via acylation and click chemistries, enable multiplexed sequencing that preserves splice junction information. Template switching onto tethered bobcodes during cDNA synthesis occurs with greater than 99% accuracy in species mixing experiments, and priming choice selects between 3'-end counting and full-length isoform capture. A BOB-seq v0.1 drug screen detects transcriptome-wide on- and off-target RNA splicing effects and outperforms existing multiplexing RNA sequencing methods in workflow simplicity, sample-to-sample variability, and barcoding accuracy.

    Why it matters: It adds isoform resolution to scalable multiplexed RNA sequencing, enabling transcriptome-wide splicing drug screens.

  8. bioRxiv Cancer Biology62

    BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING

    A common germline missense variant in BLTP3A, M1098T, impairs lysosomal stress resolution in high-grade serous ovarian cancer, prolonging STING activity and tumor-derived IFN-λ. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or the orthologous variant delayed progression and generated Cxcl9+ antigen-presenting macrophage niches, with tumor-cell STING and IFN-λ required for immune remodeling and tumor control.

    Why it matters: Links a germline variant to antitumor immunity and survival via lysosomal stress and STING.

  9. bioRxiv Cancer Biology69

    Pathway-wide base editing charts chemical-genetic interactions in MAPK signaling

    Base editor scanning across 22 MAPK genes, performed under pathway hyperactivation or inhibition at various nodes, produced a chemical-genetic interaction map of the RAS-RAF-MEK-ERK cascade. Drug resistance mutations often arose in proteins other than the direct drug target, catalytically impaired CRAF mutants gave bidirectional resistance and sensitization to structurally similar MEK inhibitors, and an allosteric site was found in the KRAS N-terminus. The work establishes BE scanning as a scalable method for network-level chemical-genetic mapping in a major oncogenic pathway.

    Why it matters: It charts chemical-genetic interactions across an oncogenic pathway and finds resistance mutations away from the drug target.

  10. bioRxiv Cancer Biology61

    A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

    Suppressive neutrophils (PMN-MDSCs) depend on mSWI/SNF chromatin remodeling to maintain their identity, and two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control in syngeneic models, including tumors resistant to PD-1 blockade. Treatment depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, enhanced checkpoint therapy without overt toxicity, and blocked PMN-MDSC expansion in mouse and human cells. Mechanistically, antagonism collapsed chromatin accessibility and PU.1/C/EBPβ occupancy at regulatory elements sustaining PMN-MDSC identity.

    Why it matters: It identifies a druggable chromatin dependency of PMN-MDSCs and shows it can restore antitumor immunity and checkpoint response.

  11. bioRxiv Cancer Biology58

    Deciphering the association of spatial landscapes of DCIS with recurrence as invasive breast cancer

    Spatial transcriptomics of 49 primary DCIS specimens shows stromal cell gradients, with TREM2+ macrophages and myofibroblastic cancer-associated fibroblasts enriched in tumor-proximal niches. TREM2+ macrophage abundance near tumor nests is associated with recurrence as invasive breast cancer, and ligand-receptor analysis implicates GRN-SORT1, SPP1-CD44, and LGALS9-CD44 signaling between these macrophages and epithelial cells. Findings were validated by multiplex immunostaining.

    Why it matters: Identifies a spatially defined stromal biomarker for progression from DCIS to invasive breast cancer.

  12. bioRxiv Cancer Biology60

    Systemic tumor-cell reprogramming converts solid tumors into in situ biofactories for immunotherapy

    LENTRA, an antigen-targeted lentiviral platform, genetically reprograms tumor cells in vivo to produce therapeutic proteins directly within the tumor after intravenous administration. In multiple murine solid tumor models, tumor-restricted expression of anti-CTLA-4 or IL-12 triggered potent antitumor responses without systemic toxicities, while sialidase secretion drove dendritic cell and T cell infiltration, macrophage reprogramming, tumor regression and durable immune memory. LENTRA also mediated efficient transduction, immune remodeling and reduced tumor viability in patient-derived tumor explants.

    Why it matters: It turns tumors into their own drug-producing biofactories, addressing toxicity of systemic delivery.

  13. bioRxiv Cancer Biology61

    Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC

    Glutaminase-1 acts as a metabolic checkpoint limiting T cell infiltration and function in head and neck squamous cell carcinoma (HNSCC). Pharmacologic inhibition or genetic deletion of glutaminase-1 increased tumor susceptibility to immune cell-mediated cytotoxicity and sensitized patient-derived tumor fragments to immune checkpoint blockade, via disruption of glutathione-dependent ROS defense, impaired tumor proliferation, and increased MHC expression. Breast cancer fragments, which show low glutaminase-1 expression, were not responsive, supporting patient stratification for metabolism-targeted immunotherapy.

    Why it matters: Identifies a targetable metabolic mechanism of immune checkpoint blockade resistance in HNSCC.

Sep 27Sun
  1. bioRxiv Genomics42

    Integrative Nanopore and Illumina sequencing reveals age-associated tRNA modification and CCA-tail dynamics in yeast

    Nanopore direct RNA sequencing (RNA004 chemistry) with Illumina validation profiles the Saccharomyces cerevisiae tRNAome during replicative aging at single-molecule resolution. Overall tRNA abundance remains largely stable, but aging brings terminal A cleavage at the 3' CCA tail of mature tRNAs, targeted T-loop and anticodon modification changes, and single-molecule evidence of modification co-occurrence. The work adds a benchmarked resource for studying tRNA regulation, translation fidelity, and longevity.

    Why it matters: It links aging to specific tRNA CCA-tail and modification changes at single-molecule resolution.

  2. bioRxiv Genomics54

    Targeted CRISPRi screening reveals unexpected resilience across the RNA polymerase III transcriptome

    An inducible CRISPR interference platform with a custom sgRNA library enabled gene-specific repression of RNA polymerase III-transcribed genes and Pol III machinery. Genome-wide screens in diploid fibroblasts and HEK293T cells uncovered several Pol III dependencies, with multiple initiator methionine tRNA genes among the strongest fitness dependencies. Glioblastoma models, however, remained largely insensitive to repression of both individual Pol III genes and core Pol III components despite efficient target knockdown, challenging the assumption that cancer cells uniformly depend on elevated Pol III activity.

    Why it matters: It shows glioblastoma models tolerate Pol III gene repression, contradicting the link between Pol III activity and cancer growth.

  3. bioRxiv Genomics62

    A single-nucleus multi-omic atlas of gene regulation across 21 adult human tissues

    A single-nucleus multi-omic atlas maps gene regulation across 21 adult human tissues from four donors, profiling 459,856 nuclei including 160,688 with paired transcriptome and chromatin accessibility. It resolves 313 subclusters and identifies 1,085,062 candidate cis-regulatory elements, 161,270 of them novel, plus 871,177 cCRE-gene links. Trained sequence-to-function models flag 18,133 high-effect fine-mapped variants, giving a framework for interpreting non-coding risk.

    Why it matters: It links regulatory DNA to cell-type-specific expression across 21 tissues and prioritizes fine-mapped non-coding variants.

Sep 26Sat
  1. bioRxiv Genomics54

    Discrepancies between ChIP-seq and CUT&Tag histone mark profiles are explained by GC content and chromatin accessibility

    Systematic comparison of ChIP-seq and CUT&Tag histone mark profiles in K562 and MCF-7 cells shows that many disagreements between the assays track GC content and chromatin accessibility. CUT&Tag loses H3K36me3 signal in GC-poor active gene bodies and H3K27me3 signal in GC-poor Polycomb-repressed domains, and promoters with discrepant H3K4me3 and H3K27ac signal differ systematically in GC content and DNase-seq and ATAC-seq signal. Studies profiling histone modification intensity and structure should account for these biases.

    Why it matters: Explains assay-dependent biases that affect interpretation of histone mark profiling comparing ChIP-seq and CUT&Tag.

Sep 25Fri
  1. medRxiv Oncology56

    Tumour extrinsic neutrophil regulation in mesothelioma correlates with responsiveness to AXL and PD1 inhibition in MIST3, a phase IIA clinical trial

    AXL and PD1 inhibition with bemcentinib plus pembrolizumab met its primary endpoint in the phase IIA MIST3 trial in ICB naïve-relapsed mesothelioma, with a 12-week disease control rate of 46.2% (90% CI 29.2-63.8%); grade 3 or greater adverse events occurred in 53.9% of patients. Multiomic analyses linked response to NF2 loss, immune response signalling, epithelial mesenchymal transition, and neutrophil-related transcriptional programmes including SPI1, ETS2 and FLI1 activation. Gut microbiota composition differed between responders and non-responders and correlated with neutrophil-associated transcription programmes, IRF3 and TLR2.

    Why it matters: Phase IIA evidence that neutrophil and gut microbiota features track response to AXL-PD1 inhibition in mesothelioma.

  2. bioRxiv Genomics51

    A single-nuclei multiomics resource across four brain regions prioritises human neural cell types influencing brain-related traits

    Single-nuclei multiomic profiling of gene expression and chromatin accessibility across ~140,000 nuclei from 40 post-mortem adult brain samples (11 donors, four regions: amygdala, hippocampus, hypothalamus, prefrontal cortex) pinpoints neural cell populations underlying brain-related traits. Integration with GWAS statistics prioritised similar neuronal populations for BMI, schizophrenia, bipolar disorder and age at menarche, and supported enhancer-gene relationships relevant to Alzheimer's disease. The resource nominates effector transcripts and cellular pathways for trait-associated variants.

    Why it matters: It maps non-coding risk variants to specific neural cell types and enhancer-gene pairs across four human brain regions.

Sep 24Thu
  1. medRxiv Oncology39

    Exploring the gut-brain axis in glioblastoma: a prospective case-control study of the gut bacteriome and mycobiome

    Newly diagnosed glioblastoma patients show altered gut bacteria and fungi: rectal-swab sequencing of 23 patients and 23 controls found both communities more diverse in patients, with Lachnospiraceae and Ruminococcaceae depleted and Methanobrevibacter and Nakaseomyces glabratus enriched. In tumor tissue, higher density of Iba1-positive myeloid cells predicted longer survival independent of age, performance status and resection extent (hazard ratio 0.82 per percentage point, 95% CI 0.67–0.99). The authors propose the myeloid compartment as the interface linking gut and tumor findings.

    Why it matters: First characterization of the gut mycobiome in glioblastoma, linking gut taxa to intratumoral myeloid cells and survival.

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org