Biology subjects

Zhu, L.

Publications and source records attributed to Zhu, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Discovery and Biosynthesis of Nitrilobacillins by Post-translational Introduction of C-Terminal Nitrile Groups

Nitrile-containing natural products are produced in all kingdoms of life. Despite the wide application of nitrile-containing peptide scaffolds in medicinal chemistry, the presence of the nitrile group is unprecedented in ribosomally synthesized and post-translationally modified peptides (RiPPs). In this work, we report the identification and characterization of a RiPP biosynthetic gene cluster (BGC), where an asparagine synthetase-like (AS-like) protein encoded in the BGC converts the C-terminal carboxylate of the precursor peptide to a nitrile. Furthermore, a multinuclear nonheme iron-dependent oxidative enzyme (MNIO) and an -ketoglutarate-dependent HExxH motif-containing enzyme (KG-HExxH) perform stereoselective {beta}-hydroxylation of aspartate and proline residues, respectively. Structure prediction-guided mechanistic evaluation of the nitrile synthetase provided insights into the possible mechanism of catalysis. These findings extend our understanding of the structural diversity of RiPPs and demonstrate the catalytic versatility of AS-like enzymes in natural product biosynthesis.

biochemistry↗

bioRxiv2026

ACENet: a graph neural network for predicting enzyme pHmin using structure and sequence insights

The acid activity of enzymes, characterized by the minimum pH at which enzymes remain active (pHmin), is crucial for industrial applications in acidic environments. However, the rational design of acid-active enzymes remains challenging due to limited understanding of sequence-structure- activity relationships under acidic conditions. Here, we propose ACENet, a graph neural network that predicts enzyme pHmin by integrating surface features of protein structures with evolutionary representations derived from the large-scale protein language model ESM-2. ACENet achieved a Pearson correlation coefficient of 0.85 on the test dataset, significantly outperforming other deep learning baseline models and maintains stable pHmin predictions under various conditions. Even on a subset of the dataset with less than 20% homology, the PCC remains above 0.5, with an RMSE (Root mean square error) less than 1.4. ACENet also present excellent performance in the annotation of pHmin for homologous proteins and the predictive screening of minimal active pH in protein mutants. Remarkably, ACENet could identify the catalytic region as key determinants of acid activity through residue-level interpretability analysis. Overall, ACENet accelerates the development of highly efficient biocatalysts for diverse applications where acidic conditions predominate.

bioinformatics↗

bioRxiv2026

Blood-brain barrier dysfunction predicts cognitive trajectory after ischemic stroke

Ischemic stroke doubles the risk of dementia.1-4 Stroke severity and location affect cognition early,5,6 but late dementia risk is not related to infarct characteristics, nor is it reduced by preventing additional strokes,3,6,7 and its mechanism is unknown. We identified a plasma proteomic signature of chronic stroke that was consistent with blood-brain barrier (BBB) dysfunction, including a 58% decrease in plasma levels of platelet-derived growth factor B and downregulation of its pathway compared to healthy controls. During 2 years of follow-up, the stroke-specific proteome was accentuated in stroke survivors who subsequently declined in the processing speed/executive function cognitive domain. To test BBB function, we performed dynamic contrast-enhanced MRI 6-9 months after stroke in an additional cohort and found 1.7-fold higher whole brain BBB leakage compared to controls. Finally, we compared autopsy tissue from people with infarcts and dementia at death to those with infarcts and no dementia. Those who died with dementia had dramatic loss of vascular mural cell coverage compared to those without dementia (median 0.7% vs. 27%). Thus, our proteomic, functional, and structural data implicate chronic BBB dysfunction in cognitive decline late after stroke, revealing potential proteomic and imaging biomarkers and, importantly, a novel target for intervention.

neuroscience↗

bioRxiv2026

Development of a recombinant adeno-associated virus vector for human T lymphocyte- and natural killer cell-targeted gene therapy

Recombinant adeno-associated virus (rAAV) vectors are widely used for gene delivery but show limited efficiency in immune cells, including T lymphocytes and natural killer (NK) cells. To overcome this barrier, we developed a modular rAAV vector engineering strategy that integrates capsid retargeting with genome optimization. We report a CD7-targeted rAAV vector (CD7-AAV6/9) featuring a nanobody-fused hybrid capsid derived from a rationally selected chimeric combination of AAV6 and AAV9. CD7-AAV6/9 enables efficient and selective transduction of immortalized and primary human T and NK cells in vitro and in vivo in a humanized mouse model, achieves high production titers, and exhibits markedly reduced off-target transduction compared with wild-type serotypes. In parallel, we demonstrate that incorporation of a human gene-derived intron into the vector genome overcomes host-mediated transcriptional repression and enables robust transgene expression in human CD7 T lymphocyte and NK cell populations. To our knowledge, this represents the first application of intron-mediated enhancement in a rAAV vector context. Together, our findings establish an integrated capsid-genome design framework for targeting human T and NK cells, notoriously challenging immune cell populations for gene therapy, and provide a versatile platform readily adaptable to alternative surface markers and therapeutic payloads.

molecular biology↗

bioRxiv2026

Universal physical principles govern the deterministic genesis of protein structure

Protein structure is usually treated as the endpoint of sequence by most AI models, yet its true biological emergence is a process of ordered change, whose logic remains hidden in opaque black box. ProtGenesis creates a bidirectional mirror world: it maps amino acid assembly, elongation and mutation in biological space into quantitative trajectories and ensembles in protein language model representation space, then translates spatial geometry into testable biophysical hypotheses. Across peptides, reporter proteins and protein families, three universal general principles emerged: hierarchical directional assembly (Principle I), quantitative and reproducible structural-emergence trajectories (Principle II) and discrete topological transitions (Principle III) from short- to long-range order. Three novel metrics of spatial features [D,{rho} ,{delta} ], complemented by squared Gaussian Wasserstein-2 measures, located structural anchors, sensitive regions and state transitions, enabling split-protein engineering and programmable protein design. ProtGenesis makes latent representations mechanistically interpretable, offering AI a route to discovering, rather than merely predicting, scientific principles. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/706798v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@18f690org.highwire.dtl.DTLVardef@e36903org.highwire.dtl.DTLVardef@35f15org.highwire.dtl.DTLVardef@1577b81_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Primary cilia regulate GLP-1 signaling in pancreatic beta cells

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the {beta}-cell response to incretins remains undefined. Here, we show that primary cilia are essential for GLP-1R signaling. Loss of {beta}-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca{superscript 2} responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in {beta} cells.

cell biology↗

bioRxiv2026

T2T Genome and Population Resequencing Reveal OfCCD4 Alleles Orchestrate Petal Color and Scent in Osmanthus fragrans

Osmanthus fragrans is prized for its floral color and fragrance, both key targets for genetic improvement. However, the lack of a complete genome assembly and comprehensive population structure hinders gene dissection and marker development for breeding. To investigate the genetic basis of color-scent interaction, a telomere-to-telomere (T2T) genome assembly is generated, and whole-genome resequencing of 100 cultivars is performed. Integrative population and metabolomic analyses reveal a trade-off: orange-red ( Aurantiacus) cultivars accumulate high /{beta}-carotene but low aromatic apocarotenoids (/{beta}-ionone), while yellow-white cultivars show the opposite pattern. Divergence mapping identifies OfCCD4 as the major underlying locus. Three alleles are characterized--functional (A), partially functional (aDel), and a frameshift null (aStop)--with aStop strictly co-segregating with the Aurantiacus phenotype. Transient and stable transformations confirm that A and aDel cleave /{beta}-carotene into /{beta}-ionone, while aStop abolishes this activity. A co-dominant PCR marker is developed based on allele-specific polymorphisms. OfCCD4 is thus established as the key regulator of the color-scent trade-off in osmanthus. The identified alleles and molecular marker enable rapid, low-cost genotyping at the seedling stage--offering particular value for marker-assisted selection in ornamental breeding, where extended juvenility makes phenotypic selection highly time- and resource-intensive.

plant biology↗

bioRxiv2026

Visualizing single base RNA mutations in living cells through DNA nanostructure mediated amplification

Capturing RNA dynamics in living cells would provide critical insights into transcriptional control and cellular adaptation, but remains technically formidable -- particularly at single-base precision. Here, we introduce a DNA tetrahedron based three-dimensional catalytic hairpin assembly (3D@CHA) nanoplatform that couples target recognition with catalytic activation in a spatially organized framework. Three cascaded hairpins (H-AN, H1, and H2) then enable localized and efficient signal amplification. Without external carriers or transfection, the platform exhibits robust biocompatibility, distinguishing highly homologous insulin I (Ins1) and insulin II (Ins2) mRNAs in living cells and tracking their redistribution and intercellular transfer during metabolic changes. Introducing a single-base mismatch site into H1 and coupling it with a Forster resonance energy transfer (FRET) readout yielded a KRAS-3D@CHA probe capable of detecting KRASG12D mutations at the RNA level with single-base resolution. This platform establishes a programmable framework for precise RNA imaging and mutation discrimination, opening new avenues for RNA-level diagnostics and precision oncology.

cell biology↗

bioRxiv2026

A structurally unique effector shared between Verticillium dahliae and Fusarium oxysporum is involved in cotton defoliation and virulence on other hosts

Defoliating (D) strains of the vascular wilt fungus Verticillium dahliae cause severe yield losses in cotton and olive worldwide, yet the genetic basis underlying this pathotype has remained unknown. Here, we combined comparative genomics, functional genetics, structural analysis, and phylogenomics to uncover the molecular determinant of defoliation. We identified a small, D pathotype-specific genomic region encoding two duplicated secreted effector genes. Simultaneous deletion of both gene copies abolished pathogenicity and defoliation in cotton, olive, Nicotiana benthamiana, and Arabidopsis thaliana, whereas single deletions reduced virulence and genetic complementation restored disease symptoms. Conversely, expression of the D effector in non-defoliating strains was sufficient to induce defoliation. Moreover, or exogenous application of the purified protein, induced wilting and defoliation as well. Structural analyses revealed that D homologs share a conserved but previously uncharacterized protein fold and are distributed across Verticillium and Fusarium species, exhibiting functional diversification and host-specific activity. Phylogenomic and genomic context analyses indicate repeated horizontal transfer events mediated by giant transposable elements known as Starships. Together, our findings identify the D effector as a central pathogenicity factor that drives defoliation and virulence, and demonstrate how Starship-mediated horizontal gene transfer shapes the emergence and dissemination of an agriculturally devastating fungal trait.

plant biology↗

bioRxiv2026

Elimination of intramuscular immunoglobulin accumulation alleviates Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disorder due to loss of dystrophin, a cytoskeletal protein critical for muscle integrity and functionality. Despite recent therapeutic advances, there remains a significant unmet need for more effective and accessible therapeutics. Here, we discovered an early accumulation of immunoglobulin G (IgG) in the sarcolemma, which exacerbates tissue inflammation and disease progression. The IgG accumulation primarily resulted from ectopic localization of Fc{gamma}R1, a high-affinity IgG Fc receptor, on dystrophin-deficient myofibers. In two independent murine models, eliminating IgG accumulation via B cell depletion provided sustained benefit to alleviate DMD progression. Our findings uncover a novel disease accelerator in DMD and demonstrate the potential to target this mechanism as therapeutics for broader population of patients with DMD.

immunology↗

bioRxiv2026

Gene contribution of Streptococcus dysgalactiae subspecies equisimilis, an emerging pathogen, to experimental primate necrotizing myositis

Streptococcus dysgalactiae subspecies equisimilis (SDSE) is an emerging human pathogen closely related to group A streptococcus. However, its genetic requirements for survival and growth in different conditions and for causing invasive infections remain poorly understood. To address this gap, we used Transposon-Directed Insertion-site Sequencing (TraDIS) to identify genes contributing to fitness in experimental necrotizing myositis in non-human primates (NHPs). Using two SDSE stG62647 human clinical isolates, MGCS36044 and MGCS36089, we generated highly saturated transposon mutant libraries and analyzed them following in vitro growth and in vivo infection in eight NHPs. We identified 398 essential genes shared by both strains during growth in vitro and in vivo, and 17 and seven conditionally essential genes required only in vitro or only in vivo, respectively. Additionally, we identified 117 and 110 genes in MGCS36044 and MGCS36089, respectively, that were associated with fitness during necrotizing myositis. Transposon insertions in 34 MGCS36044 genes conferred increased fitness, whereas mutation of 83 genes conferred decreased fitness. Similarly, in MGCS36089, mutations in 38 and 72 genes conferred increased or decreased fitness, respectively. Importantly, both strains shared 46 fitness-associated genes, including an enrichment of transporter genes, highlighting nutrient acquisition as a dominant requirement during infection. The results provide critical information for guiding future translational efforts to develop preventive and therapeutic strategies against human SDSE infections.

microbiology↗

bioRxiv2026

Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined small cell lung cancer

Combined small-cell lung cancer (cSCLC) is a rare and aggressive subtype of small-cell lung cancer (SCLC) characterized by mixed histology comprising SCLC and non-small cell lung cancer (NSCLC) or large cell neuroendocrine carcinoma (LCNEC) components. Despite its histological heterogeneity and even poorer prognosis than de novo SCLC, cSCLC is clinically managed as pure SCLC, largely due to the lack of molecular insights into its biology, lineage plasticity, and tumor microenvironment (TME). Here, we perform multi-omics profiling, including spatially-resolved whole-exome sequencing (WES), spatial transcriptomics (ST) and single-nucleus RNA sequencing (snRNA-seq), across 19 treatment-naive cSCLC tumors spanning all major histological subtypes. Our analysis reveals that SCLC and NSCLC/LCNEC components share a monoclonal origin, with histological divergence characterized by distinct mutation and copy number alteration patterns. ST and snRNA-seq uncover spatially exclusive or interspersed tumor domains, with distinct TME compositions and immune landscapes. Notably, fibroblast-rich regions enriched for an aggressive fibroblast subtype form boundaries between tumor domains, potentially influencing immune TME and treatment responses. We identify extensive lineage plasticity within cSCLC, including active LUAD-to-SCLC transdifferentiation and SCLC subtype coexistence, suggesting transitional cellular states not captured by traditional diagnostics. Leveraging these insights, we developed the cSCLC Detector, a sensitive mutation-based diagnostic assay that improves the detection of cSCLC in tissue and liquid biopsy samples. Our findings offer critical insights into cSCLC lineage plasticity, cellular evolution, and microenvironmental interactions, underscoring the need for tailored treatment strategies and diagnostic frameworks for this aggressive cancer subtype.

cancer biology↗

bioRxiv2026

Pannexin 2 restrains ER stress-induced Ca2+ dysregulation and inflammatory cardiomyocyte death

BackgroundEndoplasmic reticulum (ER) stress and ER-mitochondria Ca2+ dysregulation contribute to cardiomyocyte injury, yet endogenous regulators at ER-mitochondria interfaces that restrain this cascade remain poorly defined. Pannexin 2 (Panx2), the most structurally divergent pannexin isoform, has been implicated in stress response, but its cardiac localization and function are unclear. MethodsPanx2 localization and function were assessed in human AC16 cardiomyocytes using high-resolution confocal imaging and complementary loss- and gain-of-function approaches during thapsigargin-induced ER stress, with validation in adult mouse ventricular cardiomyocytes. ResultsPanx2 localizes predominantly to the ER and mitochondria-associated membranes, rather than the plasma membrane. Panx2 knockdown reduced ER Ca2+ stores and increased basal cytosolic and mitochondrial Ca2+. During ER stress, Panx2 deficiency markedly amplified Ca2+ dysregulation, mitochondrial dysfunction, unfolded protein response activation, and cytotoxicity, with PERK-dominant signaling and increased IRE1a activation. Notably, PERK inhibition preferentially rescued the Panx2-deficient phenotype, providing the greatest improvement in viability and reduction in cytotoxicity. Panx2 deficiency also enhanced inflammasome/ pyroptotic signaling via the NLRP3-caspase-1-gasdermin D axis. Conversely, Panx2 overexpression suppressed PERK activation and attenuated ER stress-induced injury. Panx2 ablation similarly sensitizes adult ventricular cardiomyocytes to ER stress. ConclusionsPanx2 functions as an organelle-associated checkpoint at ER-mitochondria interfaces that stabilizes Ca2+ homeostasis and limits PERK-dominant ER stress signaling and inflammatory cell death programs in cardiomyocytes, providing a mechanistic framework for cardiomyocyte loss in cardiac disease. Research PerspectiveO_ST_ABS1. What New Question Does This Study Raise?C_ST_ABSDoes Panx2 serve as an endogenous "stress threshold" determinant in cardiomyocytes in vivo, governing when ER stress transitions from adaptive signaling to PERK-driven mitochondrial failure and inflammasome-associated inflammatory cell death during cardiac injury (e.g., ischemia-reperfusion, pressure overload, or cardiometabolic stress)? 2. What Question Should Be Addressed Next?In clinically relevant models of heart disease (ischemia-reperfusion), test whether cardiomyocyte-specific Panx2 loss or augmentation alters infarct size, arrhythmia burden, ventricular remodeling, and functional recovery, and determine whether targeting the Panx2-PERK axis (e.g., selective PERK modulation in the acute reperfusion window or Panx2-directed strategies) reduces cardiomyocyte loss without impairing adaptive stress signaling needed for repair.

cell biology↗

bioRxiv2026

A dual-factor complex governs archaeal ribosome hibernation by sensing energy status

Efficient coupling of cellular energy status to ribosome regulation is fundamental for cellular survival. Here, we identify the Archaeal Ribosome regulatory Complex (ARC)--a previously uncharacterized dual-factor complex comprising ARC-P and ARC-A. Cryo-EM reveals that ARC anchors to the small ribosomal subunit, establishing a stringent blockade of the tRNA and mRNA paths via an electrostatic wedge mechanism. This hibernation state is modulated by energy status: the complex remains stably associated under low-energy conditions, whereas ATP binding triggers rapid mobilization. Genetic analyses demonstrate that ARC acts as a translational brake essential for preserving ribosomal structural integrity, with ARC-A serving as the primary inhibitory factor. Notably, while the loss of ARC accelerates growth, it impairs recovery in proportion to stress severity. Phylogenomic analysis identifies ARC as an evolutionarily novel and widely distributed dual-factor system, revealing a conserved regulatory strategy for metabolic-translational coupling across diverse archaea. Our findings define a fundamental strategy where modular complexes integrate metabolic sensing with mechanical sequestration to balance growth and persistence.

biochemistry↗

bioRxiv2026

Discovery of the Phosphonate Flavophos Produced by Burkholderia

Phosphonate natural products have proven value to society as antibiotics and herbicides. They inhibit a range of enzyme targets usually by mimicking the enzyme substrates. In this study, we investigate a family of phosphonate biosynthetic gene clusters (BGCs) found in Burkholderia. Heterologous expression in Escherichia coli resulted in production of an antimicrobial compound. Spectroscopic characterization and chemical synthesis assigned its structure as 2,4-dioxopentylphosphonic acid. One of the biosynthetic enzymes is a member of the domain of unknown function (DUF) 849 family with homology to {beta}-keto acid cleavage enzymes (BKACEs). In vitro characterization shows that this enzyme catalyzes chemistry that is divergent from previously characterized BKACEs. The observed catalytic activity is explained by a series of co-crystal structures with substrates and intermediates. The BGC also contains a gene encoding lumazine synthase (LS), an essential enzyme in flavin biosynthesis. Biochemical experiments revealed that 2,4-dioxopentylphosphonic acid inhibits LS. In addition, expression of the LS encoded in the BGC, or LS orthologs from a range of organisms, in E. coli conferred resistance to the new phosphonate, which we therefore name flavophos.

biochemistry↗

bioRxiv2026

Delta PSA: A New Metric for Conformational Dynamics Underlying Macrocyclic Peptide Permeability

Development of oral cyclic drugs often suffers from low oral bioavailability resulting from limited passive permeability making accurate prediction a central challenge in drug development. Existing approaches generally fall into two categories: deep learning-based models and accelerated molecular dynamics (aMD) simulations. While deep learning models enable rapid, high-throughput predictions, they often suffer from dependence on training data, and sensitivity to dataset biases. On the other hand, aMD provide mechanistic interpretability by explicitly modeling peptide translocation across lipid bilayers, however, suffer from huge computational cost. Here, we present a conventional MD-based framework for predicting macrocyclic peptide permeability, designed to facilitate interpretation. Importantly, we show that Delta PSA ({Delta}PSA) directly quantifies a peptides chameleon propensity, providing a mechanistically meaningful measure. Furthermore, we identify two key structural indicators--the sidechain PSA ratio and the radius of gyration--as refined metrics for assessing conformational behavior. When applied to a benchmark dataset of macrocyclic peptides, our framework achieves an MSE of 0.22, surpassing the 0.25 reported for Multi_CycGT and demonstrating its superior performance. Our work also provides a large dataset of MD trajectories for macrocyclic peptides in both polar and nonpolar environments. This dataset offers access to a broader conformational space for cyclic peptide studies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/697862v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@18fc9e4org.highwire.dtl.DTLVardef@10fbc70org.highwire.dtl.DTLVardef@1c763aorg.highwire.dtl.DTLVardef@95d9e4_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

TRPV4 Inhibition by a Natural Product Mediates Analgesia

The transient receptor potential vanilloid 4 (TRPV4) channel, a polymodal calcium-permeable cation channel, is activated by diverse stimuli, including hyposmolarity, moderate heat, mechanical stress, and acidic pH. TRPV4 plays a critical role in the onset and progression of pain and is implicated in multiple pathological conditions, positioning it as an attractive therapeutic target. However, the development of TRPV4-targeted therapeutics has been hindered by limited mechanistic understanding of its inhibition. Here, the natural product (R)-1-(3-ethylphenyl)ethane-1,2-diol (AH001) is identified as a potent, subtype-selective TRPV4 inhibitor. A potential gating mechanism of TRPV4 inhibition is proposed through a combination of structural analyses and site-directed mutagenesis. Electrophysiological studies and cryo-electron microscopy (cryo-EM) further reveal that AH001s glucuronide metabolite, AHP, retains robust TRPV4 inhibitory activity, providing a critical structural basis for rational optimization of AH001 as a lead compound. Notably, AH001 demonstrated significant efficacy in reducing neuronal hyperexcitability in dorsal root ganglia (DRGs) and produced pronounced analgesic effects across multiple pain models, highlighting its therapeutic potential in pain relief. This study offers critical structural and mechanistic insights into TRPV4 inhibition and lays the groundwork for the structure-based design of TRPV4-targeted therapeutics.

biochemistry↗

bioRxiv2025

Pan-cancer tumor classification by a holistic tumor microenvironment atlas

The tumor microenvironment (TME) heterogeneity presents a major bottleneck to effective cancer immunotherapies. We address this by establishing a pan-cancer tumor classification system based on the holistic TME cellular components. First, using single-cell transcriptomes from 1,271 patients across 26 cancer types, we compile a TME cellular atlas, leading to the identification of recurrent cell states and multicellular modules across cancer types. Among these, we highlight a type I interferon (IFN-I)-related multicellular module, including IFIT1+ tumor-associated macrophages, as a critical contributor to immune-activation TMEs. From a holistic perspective, pan-cancer TMEs exhibit trichotomous patterns predominantly driven by T, myeloid, and stromal compartments. Leveraging fine-grained TME cellular composition, we further stratify all tumors into 10 stable groups. These groups display varying responses to immune checkpoint blockade (ICB), and each rationally selected therapeutic strategy specifically perturbs the corresponding expression signature. Our pan-cancer tumor classification scheme reveals the underlying patterns of TME heterogeneity and provides a framework for stratifying patients, guiding treatment selection, and developing novel therapeutic options.

cancer biology↗