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PubMed2026

Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.

Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Amyotrophic Lateral Sclerosis↗
PubMed2026

Pan-genomics and multi-omics for deciphering genetic variation and accelerating genetic improvement in ruminant livestock.

Livestock reference genomes have transformed the discovery of variants associated with production, reproduction, health, and environmental adaptation. Nevertheless, a single linear reference represents only one mosaic haplotype and incompletely captures sequence diversity within a species, particularly structural variants, copy-number changes, repeat-rich regions, and breed-specific sequences. Pangenomes address this limitation by integrating multiple high-quality assemblies or population-scale variants into a unified sequence or graph representation. Concurrently, multi-omics approaches connect genomic variation with transcriptomic, epigenomic, manuscriptproteomic, metabolomic, and microbiome responses, thereby improving biological interpretation of genotype-phenotype relationships. This review synthesizes recent progress in livestock pangenomics and multi-omics, with emphasis on cattle, goats, sheep, water buffalo, and chickens. It describes advances in long-read and haplotype-resolved sequencing, graph construction, structural-variant discovery and genotyping, functional annotation, and integrative analysis. Recent pangenome studies have uncovered substantial non-reference sequence, reduced reference bias, identified breed- and population-specific structural variants, and resolved candidate variants underlying pigmentation, body size, tail morphology, cashmere production, altitude adaptation, and other economically relevant traits. However, translation into routine breeding remains constrained by uneven population representation, inconsistent structural-variant definitions, limited functional annotation, computational demands, and insufficient validation across environments. Future progress will depend on diverse near-complete assemblies, graph-aware imputation and genomic prediction, long-read transcriptomics, single-cell and spatial omics, rigorous causal validation, and open, interoperable resources. Together, these developments can support more accurate, resilient, and biologically informed livestock improvement. Importantly, current dairy-cattle evidence indicates that pangenome-derived structural variants can substantially improve variant discovery and functional interpretation while yielding only marginal average gains in routine genomic prediction, favoring targeted augmentation rather than wholesale replacement of established SNP-based evaluations.

Animals↗
PubMed2026

Pancreatic ductal adenocarcinoma: The Vision of Heracles.

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, as tumors evolve faster than therapies. Resistance is ecological, not merely KRAS driven, involving overlooked players like high-grade pancreatic intraepithelial neoplasias (PanINs), peripancreatic fat, stromal mechanics, myeloid-neural circuits, metabolic rewiring, and systemic host responses. We propose precision interception targeting PanIN/intraductal papillary mucinous neoplasm (IPMN) biology, spatial-functional-proteogenomic classification beyond transcriptomics, the Heracles Protocol (measure, prime, strike, and adapt), and integrated technologies from AI pathology to exosomal delivery and CRISPR-based synergy mapping, together making PDAC more tractable.

Humans↗
PubMed2026

Hormone priming and metabolic engineering of phytohormone crosstalk in rice under combined biotic and abiotic stresses: a multi-omics perspective for climate-resilient crop development.

Rice (Oryza sativa L.) is the caloric backbone for more than half of humanity, yet it remains one of the most vulnerable crops to the simultaneous biotic and abiotic stresses exacerbated by climate change. Phytohormone priming and the complex crosstalk networks governed by transcription factor hubs like WRKY, MYB, and NAC serve as the central adaptive mechanism for stress resilience. This review synthesizes how multi-omics integration, including spatial and single-cell transcriptomics, is resolving the molecular architecture of hormonal priming and epigenetic stress memory. We critically evaluate advanced metabolic engineering and genome-editing strategies such as CRISPR-Cas9, base/prime editing, and synthetic gene circuits that enable precision modifications to decouple stress tolerance from historical yield penalties. Furthermore, we discuss the emerging roles of microbiome-assisted priming via synthetic consortia and the application of artificial intelligence and digital twins (continuously updated computational models of crop physiology) for predictive stress management. By integrating these diverse technological pillars, we propose a systems-level roadmap for developing climate-resilient rice cultivars capable of maintaining yield stability across a volatile combinatorial stress landscape. This synthesis provides a framework for translating mechanistic hormonal insights into field-applicable cultivars to ensure global food security.

CRISPR↗
PubMed2026

Multimodal atlas of human atherosclerosis links granular vascular cell states to coronary artery disease risk.

Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.

Journal Article↗
PubMed2025

Combined somatic mutation and transcriptome analysis reveals region-specific differences in clonal architecture in human cortex.

The human cerebral cortex is specialized into regions, but little is known about how human cellular lineages shape cortical regional variation and neuronal cell-type distribution during development. Here, we map single-cell lineages of human cortical regions and neuronal subtypes using >1,000 somatic single-nucleotide variants (sSNVs) identified from deep bulk whole-genome sequencing and analyzed over 25 regions and >72,000 single cells. In the fronto-parietal cortex, sSNVs are rarely restricted, marking neuron-generating clones that disperse into neighboring regions. In contrast, the primary visual cortex harbors 30%-70% more sSNVs than the neighboring secondary visual cortex. Clones at this border exhibit more restricted dispersion, suggesting late developmental lineage segregation. Single-nucleus sSNV and whole-transcriptome analysis reveal glutamatergic neuron clones with modest regional restrictions that share low-mosaic sSNVs with some GABAergic neurons, suggesting a recent dorsal cortical progenitor. Our analysis reveals human-specific cortical lineage patterns, regional differences in clonal patterns, and late divergence of some glutamatergic/GABAergic lineages.

Humans↗
PubMed2025

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

Animals↗
PubMed2026

Multi‑omics approaches to decipher the molecular mechanisms of exercise‑mediated bone protection: From mechanistic insights to personalized exercise prescription (Review).

The global burden of bone metabolic disorders necessitates a shift from generic exercise recommendations toward personalized prescription strategies. Exercise confers skeletal protection through mechanotransduction, yet the underlying molecular networks remain incompletely understood. Multi‑omics technologies, including transcriptomics, proteomics, metabolomics and single‑cell spatial approaches, have revolutionized the capacity to decode exercise‑mediated bone adaptation at the systems level. The present review synthesizes current single‑omics landscapes and integrative multi‑omics analyses that elucidate the core regulatory networks, mechanobiological coupling mechanisms and multiorgan crosstalk that are implicated in the bone response to mechanical loading. Translational applications across clinical scenarios such as osteoporosis, osteoarthritis and disuse bone loss are evaluated, and the technical, analytical and translational challenges limiting clinical implementation are addressed. Finally, the present review provides a framework for translating multi‑omics molecular signatures into personalized exercise prescriptions for optimized skeletal health.

Humans↗
PubMed2026

Moving Beyond Morphology to Multiplexed Molecular Imaging as the Next Frontier in Diagnostic Pathology.

Diagnostic pathology has long relied on the morphologic interpretation of hematoxylin and eosin-stained tissues to guide diagnosis and assess prognostic features. Although pathologists intuitively recognize spatial patterns and architectural organization, these assessments remain largely qualitative and difficult to quantify systematically. Immunohistochemistry and immunofluorescence have introduced molecular specificity but are limited in multiplexing capacity, whereas bulk genomic and transcriptomic assays provide high molecular depth but lose spatial context by averaging signals across heterogeneous cell populations. Recent advances in spatial proteomics-including mass spectrometry-based imaging and cyclic immunofluorescence-now enable multiplexed, single-cell protein analysis within intact tissue architecture. These technologies have revealed complex immune and stromal microenvironments, spatially organized biomarkers predictive of therapeutic response, and molecular gradients underlying disease progression. By integrating histologic and molecular information, spatial proteomics bridges traditional microscopy with high-dimensional omics, allowing quantitative, spatially resolved insights into tissue organization and disease mechanisms. This review summarizes recent developments in multiplexed spatial proteomics from both scientific and pathologic perspectives, highlighting how these technologies extend beyond morphology to quantify histologic patterns, refine biomarker discovery, and facilitate clinical translation. The review also examines translational challenges and barriers to clinical implementation, including costs, standardization requirements, and workflow integration.

Humans↗
PubMed2026

Beyond the gene: isoform diversity as a key contributor to human brain disorders.

The human brain exhibits exceptional transcriptomic complexity, with alternative splicing, promoter usage, and polyadenylation generating extensive transcript-isoform diversity. Isoform dysregulation is increasingly implicated in neurodevelopmental and psychiatric disorders (NPDs), yet the landscape, function, and genetic regulation of brain isoforms remain poorly understood due to limitations of short-read RNA sequencing. Advances in long-read sequencing (LR-seq) enable scalable full-length transcriptome profiling with single-cell and spatial resolution across developmental stages. Here, we review recent progress in isoform discovery, quantification, functional annotation, and genetic regulation, highlighting emerging links to human neurodevelopment and disease. LR-seq studies have uncovered tens of thousands of previously unannotated brain isoforms, with neuronal maturation characterized by increased exon inclusion and progressive 3' untranslated region (3' UTR) lengthening. Isoform-resolved genetic mapping outperforms gene-level analyses for NPD gene discovery and mechanistic interpretation. We argue that a shift from gene-centric to isoform-centric frameworks is essential to fully capture regulatory complexity in human neurogenetics. Together, these advances establish isoform diversity as a fundamental yet underappreciated axis of brain gene regulation and a key entry point for dissecting NPD biology.

Humans↗
PubMed2026

Decoding the spatiotemporal patterns of food spoilage microbial communities: Integrating multi-omics and artificial intelligence to enable precision preservation.

In the global food supply chain, food wastage caused by spoilage has resulted in significant economic losses, food shortages, and environmental pressure. This process is fundamentally driven by the spatiotemporal dynamics of microbial communities. However, traditional research methods struggle to elucidate the complex mechanisms of spatial heterogeneity, interspecies interactions, and functional succession. This limits the development of effective preservation strategies. This review systematically reviews the cutting-edge progress of integrating multi-omics technologies and artificial intelligence (AI) to study food spoilage microbial communities, breaking through this bottleneck. We propose an intelligent theoretical framework that could potentially analyze microbial metabolic activities and predict dynamic shelf life if implemented. The conceptual framework integrates multidimensional data, including spatial metabolomics, temporal metatranscriptomics, single-cell transcriptomics, and longitudinal metagenomics. It can also be combined with AI models, such as graph neural networks. The article elaborates on the principles and applications of spatio-temporal monitoring technologies, such as nano secondary ion mass spectrometry, hyperspectral imaging, and the Internet of Things sensing. Through illustrative cases of typical perishable foods, it also explores how such a multi-omics - AI system might be applied to spoilage warning and precise intervention. Additionally, the article addresses the current challenges in data coverage, model generalization, and federated learning implementation. Then the research further explores emerging areas such as engineered probiotics, edge AI, and microfluidic sensing. These areas are targeted at transforming food preservation from an empirical control approach to a data-driven, precise regulatory framework. This transformation provides theoretical support and technical approaches for developing a smart, sustainable food preservation system.

Multiomics↗
PubMed2026

Perineuronal net degradation in aggressive glioblastomas with KANK1::NTRK2 fusions.

BACKGROUND: Approximately 10% of glioblastomas harbor targetable genomic fusions. NTRK2 participates in a variety of fusion events that drive tumorigenesis. Two previous reports have described KANK1::NTRK2 fusions in adult glioblastoma patients with poor survival. METHODS: We performed a retrospective analysis of glioblastoma patients treated at Dartmouth-Hitchcock Medical Center (DHMC) from 2020 to 2025 to identify cases harboring KANK1::NTRK2 fusions. Clinical presentation, treatment, histopathologic features, and outcomes were reviewed. In addition, we conducted GeoMx whole-transcriptome and high-plex proteomic digital spatial profiling of a KANK1::NTRK2-positive glioblastoma and a comparator tumor from a long-term survivor. Candidate biomarkers were orthogonally validated using immunohistochemistry and/or immunofluorescence. RESULTS: Two patients with KANK1::NTRK2 fusion glioblastoma were identified, both demonstrating rapid progression, therapeutic resistance, and survival of less than 7 months. Proteomic profiling showed increased expression and activation of canonical NTRK2 downstream signaling pathways, particularly MEK1/2 and ERK1/2. This was accompanied by upregulation of extracellular matrix remodeling enzymes, including MMP3, MMP14, and ADAM15, along with reduced expression of extracellular matrix-associated transcripts and perineuronal net components in particular compared to a non-fusion glioblastoma. CONCLUSIONS: These limited, hypothesis-generating findings suggest constitutive NTRK2 signaling may promote coordinated extracellular matrix degradation and remodeling, potentially facilitating rapid and aggressive tumor growth and invasion in a subset of glioblastomas.

NTRK gene fusion↗
PubMed2026

Omics in optic neuropathies: From molecular landscapes to personalized therapeutics.

Optic neuropathies comprise a heterogeneous group of disorders involving transient or permanent injury to retinal ganglion cells (RGCs) and their axons. Clinically, these neurodegenerative conditions manifest as dyschromatopsia, decreased visual acuity, and visual field defects, and in severe cases may ultimately lead to blindness and disability. The marked heterogeneity across disease subtypes, incompletely understood etiologies, and complex pathogenic mechanisms pose substantial challenges to precise diagnosis and effective treatment. Recent advances in omics technologies - including genomics, transcriptomics, proteomics, metabolomics, lipidomics, single-cell and spatial sequencing, and integrative multi-omics approaches - have ushered optic nerve degenerative disease research into an era of high-resolution comprehensive investigation. In this review, we summarize representative applications of omics approaches to elucidate genetic alterations, signaling dysregulation, metabolic reprogramming, and immune responses in optic neuropathies. We further discuss the emerging potential of multi-omics in identifying early diagnostic biomarkers and informing individualized therapeutic strategies. Finally, we provide a forward-looking perspective on the future trajectory of omics technologies and their prospects in both fundamental research and clinical translation, with the overarching aim of accelerating the bench-to-bedside transition in this critical eye disease field.

biomarkers↗
PubMed2026

Selective saccular plasticity under microgravity links peripheral transcriptomic remodeling to postflight vestibular dysfunction.

Long-duration exposure to microgravity disrupts human balance and spatial orientation, yet the molecular mechanisms underlying vestibular adaptation to spaceflight remain poorly understood. Here, we tested the hypothesis that the saccule, the primary gravity-sensing otolith organ, undergoes selective remodeling during spaceflight and contributes to transient postflight postural instability. Using a cross-species approach, we combined transcriptomic analysis of mouse otolith organs with physiological assessments in astronauts. Laser microdissection-based RNA sequencing of mouse otolith sensory epithelia after a 35-d spaceflight revealed pronounced, organ-specific transcriptomic remodeling in the saccule, whereas the utricle remained stable. Principal component and clustering analyses demonstrated that the saccular transcriptome shifted toward an utricle-like profile under microgravity, accompanied by changes in genes related to synaptic and neuronal function. Promoter motif analysis identified NFAT-associated transcriptional networks, suggesting Ca2+-dependent regulation of synaptic plasticity as a potential molecular substrate of gravity-dependent adaptation. In parallel, vestibular testing in astronauts following long-duration missions (157 to 328 d) revealed selective attenuation of saccule-mediated cervical vestibular-evoked myogenic potentials and increased postural sway immediately after return to Earth, while utricle-mediated responses and semicircular canal function were preserved. Both saccular function and postural stability recovered within approximately 10 d. Notably, early postflight postural instability was partially mitigated by noisy galvanic vestibular stimulation, consistent with stochastic resonance-mediated sensory enhancement. Together, these findings identify the saccule as a plastic gravity sensor and establish a mechanistic link between peripheral molecular remodeling and functional balance deficits after spaceflight, providing a framework for developing countermeasures to facilitate vestibular readaptation during human space exploration.

Animals↗
PubMed2026

DREAMS illuminates spatial DNA and RNA modification landscapes.

DNA and RNA modifications regulate gene expression and RNA processing, but their spatial organization in complex tissues remains elusive. Here we developed DNA RNA Elements Areal Mass Spectrometry (DREAMS), a mass spectrometry imaging platform that spatially maps diverse nucleic acid modifications simultaneously. Applying DREAMS to TET-deficient mouse brains (Tet1Δ/Δ and triple Tet1/2/3Δ/Δ), we uncover TET1's unexpected role in modulating N1-methyladenosine (m1A), a pivotal RNA modification. While DREAMS reveals broad modification landscapes altered across TET knockouts, we identify TET1-mediated changes in m1A that correlate with transcriptome alterations. Our work establishes DREAMS as a transformative tool for spatial epigenomics/epitranscriptomics and suggests that TET enzymes could influence multiple DNA and RNA modifications with potential gatekeeping roles in nucleic acid regulation.

Animals↗
PubMed2026

Cyclin-dependent kinase 4 and 6 inhibitors and the breast cancer immune ecosystem: immune remodeling, resistance, and therapeutic reprogramming.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) combined with endocrine therapy have become a therapeutic backbone for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, yet durable disease control is frequently limited by intrinsic and acquired resistance. Canonical tumor-cell mechanisms, including retinoblastoma-pathway escape, cyclin E-cyclin-dependent kinase 2 (CDK2) activation, endocrine adaptation, and phosphoinositide 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling, explain only part of this failure because they do not fully capture dynamic immune and stromal remodeling. Preclinical and translational studies indicate that early CDK4/6 inhibition can enhance antigen presentation, activate interferon-related programs, restrain regulatory T cells, and promote a T-cell-inflamed state. These effects are conditional and may not persist during prolonged treatment. Sustained therapy can instead drive heterogeneous resistant niches characterized by stromal remodeling, myeloid recruitment, checkpoint adaptation, and T-cell dysfunction. This immune-state dependence provides a rationale for immune checkpoint blockade, although clinical combinations have shown mixed efficacy and clinically relevant hepatic, pulmonary, and hematologic toxicities. Sequential or lead-in strategies therefore warrant prospective evaluation. Oxidative phosphorylation (OXPHOS) and redox adaptation may sustain selected resistant states and expose context-dependent ferroptotic vulnerabilities. Ferroptosis may connect tumor-cell killing with immune regulation, whereas nanomedicine may improve tumor-selective delivery. Both strategies remain largely preclinical and require further evaluation of pharmacokinetics, biodistribution, toxicity, manufacturability, and immune-cell safety. This Review distinguishes intrinsic from acquired resistance across interpatient, intratumoral, spatial, and temporal dimensions. It integrates tumor-cell escape with cytokine, immune, stromal, vascular, and metabolic remodeling and summarizes emerging therapeutic strategies. We further propose a candidate biomarker-informed framework that integrates genomic profiling, spatial immune architecture, circulating biomarkers, T-cell receptor (TCR) dynamics, transcriptomic and single-cell analyses, artificial intelligence (AI)-assisted multimodal integration, and longitudinal sampling. This framework is intended to support biomarker development and prospective trial design rather than current clinical decision-making, providing a translational basis for testing state-informed and sequence-aware therapeutic strategies.

Humans↗
PubMed2026

Gata3 dosage governs primitive endoderm versus trophectoderm specification in embryonic stem cells.

Transcription factor (TF) dosage represents an overlooked aspect of developmental regulation. While Gata3 has traditionally been viewed as a determinant of trophectoderm (TE), its potential role in primitive endoderm (PE) has remained unclear. Here, we demonstrate that Gata3 functions as a dosage-sensitive regulator directing mutually exclusive lineage programs in mouse embryonic stem (ES) cells. Low levels of Gata3 (Gata3-L) promote PE-like transcriptional states, while high levels (Gata3-H) drive TE identity by rapidly repressing pluripotency and inducing TE markers. Genome-wide binding analysis reveals a dose-dependent redistribution of Gata3 across enhancers, with chromatin engagement consistent with pioneer factor-like activity. Functional 3D blastoid assays combined with single-cell transcriptomics further establish that Gata3 dosage alone is sufficient to instruct the spatial segregation of PE- versus TE-like compartments. These findings redefine Gata3 not merely as a TE determinant but as a central dosage-sensitive switch in lineage specification. More broadly, our results position TF dosage as a fundamental regulatory parameter that integrates enhancer selection, chromatin engagement, and spatial patterning, providing new opportunities to refine stem cell-based models and engineer developmental outcomes.

GATA3 Transcription Factor↗
PubMed2026

Menopausal timing and senescent-immune coupling in age-related lobular involution of the human breast: a longitudinal cohort study.

BACKGROUND: Incomplete postmenopausal breast involution leaves persistent epithelial-rich lobules and elevated breast density in about 40% of women and is associated with higher breast cancer risk, but why remodelling stalls remains unclear. METHODS: We studied a longitudinal cohort of 81 women with paired benign breast biopsies (baseline age 45-55 years; follow-up 2-10 years), all with baseline NanoString transcriptomics and two-timepoint digital morphometry, and with multiplex immunofluorescence in spatial-imaging subsets (baseline n = 14-16 depending on panel; follow-up n = 14). A separate postmenopausal endpoint cohort (12 women: eight noninvoluted, four completely involuted), profiled by genome-wide expression array and multiplex immunofluorescence, defined the persistent-lobule phenotype. FINDINGS: Noninvoluted postmenopausal tissue retained a proliferation-competent, tumour-associated epithelial state and showed immune accumulation at lobular boundaries with reduced access to p16+ (senescence-associated) epithelial foci. The same SASP and innate immune programmes that predicted slower involution across the menopausal transition predicted faster involution after menopause. Follow-up boundary CD45→p16 engagement was directionally consistent with this reversal in Pre→Post and Post→Post women. Spatial imaging resolved this reversal into a perimenopausal stall architecture and a postmenopausal clearance-associated architecture marked by direct CD16+ innate-effector engagement of p16+ epithelium; macrophage targeting provided convergent support (two-sided exact permutation interaction p = 0.0077). INTERPRETATION: Menopausal timing conditions whether senescent-immune programmes couple to productive clearance or to spatially uncoupled surveillance and persistent risk-associated tissue. Biomarker interpretation should therefore be anchored to menopausal timing. FUNDING: Casey DeSantis Cancer Fund and US National Cancer Institute.

Humans↗