bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–03–29
nineteen papers selected by
Xiao Qin, University of Oxford
  1. Epigenetic memory of colitis promotes tumour growth.
  2. Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
  3. Defining a Multi-Omic, AI-Enabled Stool Screening Paradigm for Colorectal Cancer: A Consensus Framework for Clinical Translation.
  4. Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
  5. Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis.
  6. A cross-kingdom alliance driving colorectal cancer.
  7. Progress and new challenges in image-based profiling.
  8. p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration.
  9. Hyperinnervation inhibits organ-level regeneration in mammalian skin.
  10. Remembrance of inflammations past.
  11. Toward Computationally Complete Spatial Omics.
  12. In vivo interrogation of transcriptional and epigenetic regulators of lung epithelial regeneration.
  13. AI scientists are changing research - institutions, funders and publishers must respond.
  14. How to build an AI scientist: first peer-reviewed paper spills the secrets.
  15. Immunometabolic gatekeeping: How tissue metabolism conditions tumor immunity.
  16. Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
  17. Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target.
  18. Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
  19. Striking the right balance with type I interferon signalling in cancer.
  1. Nature. 2026 Mar 25.
    Epigenetic memory of colitis promotes tumour growth.
    Surya Nagaraja, Lety Ojeda-Miron, Ruochi Zhang, Ena Oreskovic, Conrad Hock, Yan Hu, Daniel Zeve, Karina Sharma, Roni R Hyman, Qiming Zhang, Andrew Castillo, David T Breault, Ömer H Yilmaz, Jason D Buenrostro.
      Chronic inflammation is a well-established risk factor for cancer, but the underlying molecular mechanisms remain unclear1,2. Using a mouse model of colitis, we demonstrate that colonic stem cells retain an epigenetic memory of inflammation following disease resolution that persists for more than 100 days. Here we find that memory of colitis is characterized by a cumulative gain of activator protein 1 (AP-1) transcription factor activity, with durable changes to chromatin accessibility. Further, we develop SHARE-TRACE, a method that enables simultaneous profiling of gene expression, chromatin accessibility and clonal history in single cells, enabling high-resolution tracking of epigenomic memory. This approach reveals that memory of colitis is propagated cell-intrinsically and inherited through stem cell divisions, with some clones demonstrating stronger memory than others. Finally, we show that colitis primes stem cells for increased expression of an AP-1-regulated gene program following oncogenic mutation that accelerates tumour growth, a phenotype dependent on AP-1 activity. Together, our findings provide a mechanistic link between chronic inflammation and malignancy, revealing how long-lived epigenetic alterations in regenerative tissues may contribute to disease susceptibility and suggesting potential diagnostic and therapeutic strategies to mitigate cancer risk in patients with chronic inflammatory conditions.
    DOI:  https://doi.org/10.1038/s41586-026-10258-4
  2. Dev Cell. 2026 Mar 23. pii: S1534-5807(26)00082-1. [Epub ahead of print]
    Disruption of WNT/Notch signaling in pancreatic cancer reveals tumors depend on the intricate equilibrium of malignant cell states.
    Stefan R Torborg, Jung Yun Kim, Anupriya Singhal, Olivera Grbovic-Huezo, Matilda Holm, Katherine Wu, Xuexiang Han, Yu-Jui Ho, Caj Haglund, Michael J Mitchell, Scott W Lowe, Lukas E Dow, Kenneth L Pitter, Francisco J Sanchez-Rivera, Andre Levchenko, Tuomas Tammela.
      Control of cell identity and number is central to tissue function, yet principles governing the organization of malignant cells remain poorly understood. Using genetically engineered mouse models and orthotopic allografts with dual WNT reporter systems, we discover that pancreatic ductal adenocarcinoma (PDAC) organizes in a stereotypical pattern, whereby PDAC cells responding to WNT signals (WNT-R) neighbor WNT-secreting cancer cells (WNT-S). Lineage tracing reveals that the WNT-R state is transient and gives rise to a stable WNT-S state. A subset of WNT-S cells expressing DLL1 forms a functional niche for WNT-R cells. The genetic inactivation of WNT secretion or Notch pathway components, or the cytoablation of WNT-S cells, disrupts PDAC tissue organization, suppressing tumor growth and metastasis. Analysis of human PDAC tissues confirms conservation of these populations. PDAC growth depends on an intricately controlled equilibrium of functionally distinct cancer cell states, revealing the fundamental principles governing solid tumor organization and therapeutic opportunities.
    Keywords:  Notch; WNT; gene perturbation; intratumoral heterogeneity; lineage ablation; lineage tracing; pancreas cancer; tissue organization
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.017
  3. Cancers (Basel). 2026 Mar 11. pii: 909. [Epub ahead of print]18(6):
    Defining a Multi-Omic, AI-Enabled Stool Screening Paradigm for Colorectal Cancer: A Consensus Framework for Clinical Translation.
    Arturo Loaiza-Bonilla, Yan Leyfman, Viviana Cortiana, Rhys Crawford, Shivani Modi.
      Colorectal cancer (CRC) develops through both conventional adenoma-carcinoma and serrated neoplasia pathways, yet noninvasive screening still under-detects the advanced precursor lesions that enable true cancer prevention. Stool-based screening reduces CRC mortality, but its preventive impact remains constrained by limited detection of advanced precancerous lesions (APLs), including advanced adenomas and sessile serrated lesions. Next-generation multitarget stool DNA assays (mt-sDNA; e.g., Cologuard Plus) have established high sensitivity for CRC and specificity approaching 94%, leaving improved APL detection as the principal opportunity for innovation. This review presents a consensus framework for a multi-omic stool screening paradigm that integrates host epigenetic markers (DNA methylation) with gut microbiome features using artificial intelligence (AI). Multi-omics capture complementary layers of early tumor biology: epithelial shedding and field effects reflected in host methylation signals together with luminal ecological and inflammatory changes represented by microbial features. Evidence from cross-cohort microbiome studies indicates that microbial signatures provide an additive-rather than standalone-axis of information for CRC and its precursor lesions. Because microbiome-based models are highly susceptible to batch effects arising from collection devices, extraction chemistry, sequencing platforms, and bioinformatic pipelines, practical mitigation strategies are outlined, including harmonized pre-analytics, batch-aware study design, leakage-resistant validation, and computational harmonization. A translational roadmap linking analytical validity, locked-model development, and prospective colonoscopy-verified clinical validation is proposed, aligned with TRIPOD + AI, STARD, PROBAST-AI, SPIRIT-AI, CONSORT-AI, and DECIDE-AI reporting standards. Scenario modeling using BLUE-C prevalence estimates suggests that improving APL sensitivity from approximately 43% to 55-65% at ~94% specificity could translate to detecting roughly 13-23 additional advanced precancerous lesions per 1000 individuals screened, highlighting the potential prevention impact of a multi-omic approach. This framework aims to guide developers and clinical investigators toward next-generation stool tests capable of materially improving precursor-lesion detection while maintaining clinically acceptable specificity.
    Keywords:  artificial intelligence; cancer prevention; colorectal cancer screening; diagnostic accuracy reporting; gut microbiome; host DNA methylation; multi-omic biomarkers; multitarget stool DNA
    DOI:  https://doi.org/10.3390/cancers18060909
  4. Trends Cancer. 2026 Mar 24. pii: S2405-8033(26)00038-5. [Epub ahead of print]
    Watching cancer begin: emerging tools to visualize the first steps of tumorigenesis.
    Hendrik A Messal, Larissa Mourao, Lea Dörner, Colinda L G J Scheele, Jacco van Rheenen.
      Understanding tumor initiation is crucial for early interception and prevention. Tumors arise from genetic alterations and microenvironmental changes that together create a niche for malignant growth. Previously, the spatiotemporal dynamics of tumorigenesis were difficult to study. Recent advances in high-resolution intravital microscopy, tissue clearing, and spatial molecular profiling enable direct visualization of mutated cells and clones within their microenvironment in situ. These tools transform tumor initiation from a theoretical construct into a mechanistically dissectible process. Here, we synthesize recent insights into how mutated clones expand or regress, how clonal dynamics drive transformation, and how niche signals shape tumor-initiating cell fate. We highlight key imaging innovations and outline limitations and opportunities for capturing tumor initiation in vivo.
    Keywords:  clonal dynamics; intravital microscopy; spatial transcriptomics; tissue clearing; tumor initiation; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.007
  5. bioRxiv. 2026 Mar 16. pii: 2026.03.15.711939. [Epub ahead of print]
    Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis.
    Gourab Lahiri, Yesenia Barrera Millan, Swathi Sankar, Karla Mullen, Thomas Hartley McDermott, Dominic R Saiz, Fiona Farnsworth, Matt Torel, Madeline Blatt, Ana Cristina Roginski, Abhigyan Shukla, Esther Florsheim, Benjamin B Bartelle, Khashayarsha Khazaie, Fotini Gounari, Miyeko D Mana.
      Maternal obesity is associated with increased risk of sporadic colorectal cancer (CRC) in offspring, suggesting that early-life environmental exposures durably shape disease susceptibility. Intestinal stem cells (ISCs), long-lived drivers of epithelial renewal and tumor initiation, are well poised to mediate this effect; however, how maternal obesity influences ISC programming during development remains poorly understood. Using mouse models of diet-induced obesity, we show that exposure to a maternal high-fat Western diet (mHFD) during pre- and postnatal development stably programs colonic ISCs. Offspring exhibit increased ISC proliferation, enhanced self-renewal, a hypermetabolic state, and altered epithelial lineage composition that persists into adulthood despite dietary normalization. These changes are accompanied by increased tumor burden following loss of Apc heterozygosity. Mechanistically, we identify the pro-inflammatory cytokine IL-17A as a key extrinsic driver and PPARd/a nuclear receptors as intrinsic mediators of the mHFD phenotype, revealing an immune-epithelial axis that programs ISC function during early life. Together, our findings demonstrate that maternal metabolic environments durably enhance stem cell fitness, providing a mechanistic link between developmental exposure and adult disease risk.
    DOI:  https://doi.org/10.64898/2026.03.15.711939
  6. Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00158-3. [Epub ahead of print]
    A cross-kingdom alliance driving colorectal cancer.
    Lior Lobel.
      In this issue of Cancer Cell, Li et al. show that Candida albicans and Fusobacterium nucleatum form a cross-kingdom interaction through Flo9-RadD binding that accelerates colorectal cancer (CRC) progression. Disrupting this interaction with L-arginine reduces tumor burden, highlighting targeting microbial cooperation as a potential therapeutic strategy for CRC.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.006
  7. Mol Syst Biol. 2026 Mar 27.
    Progress and new challenges in image-based profiling.
    Erik Serrano, John Peters, Jesko Wagner, Rebecca E Graham, Zhenghao Chen, Brian Y Feng, Gisele Miranda, Alexandr A Kalinin, Loan Vulliard, Jenna Tomkinson, Cameron Mattson, Michael J Lippincott, Ziqi Kang, Divya Sitani, Dave Bunten, Srijit Seal, Neil O Carragher, Anne E Carpenter, Shantanu Singh, Paula A Marin Zapata, Juan C Caicedo, Gregory P Way.
      For over two decades, image-based profiling has revolutionized cell phenotype analysis. Image-based profiling processes rich, high-throughput, microscopy data into thousands of unbiased measurements that reveal phenotypic patterns powerful for drug discovery, functional genomics, and cell state classification. Here, we review the evolving computational landscape of image-based profiling, detailing the bioinformatics processes involved from feature extraction to normalization and batch correction. We discuss how deep learning has fundamentally reshaped the field. We examine key methodological advancements, such as single-cell analysis, the development of robust similarity metrics, and the expansion into new modalities like optical pooled screening, temporal imaging, and 3D organoid profiling. We also highlight the growth of public benchmarks and open-source software ecosystems as a key driver for fostering reproducibility and collaboration. Despite these advances, the field still faces substantial challenges, particularly in developing methods for emerging temporal and 3D data modalities, establishing robust quality control standards and workflows, and interpreting the processed features. By focusing on the technical evolution of image-based profiling rather than the wide-ranging biological applications, our aim with this review is to provide researchers with a roadmap for navigating the progress and new challenges in this rapidly advancing domain.
    Keywords:  Cell Profiling; Deep Learning; Feature Extraction; Image-Based Profiling; Phenotypic Screening
    DOI:  https://doi.org/10.1038/s44320-026-00197-7
  8. Trends Cancer. 2026 Mar 25. pii: S2405-8033(26)00035-X. [Epub ahead of print]
    p53: defender of lineage fidelity and foe of plasticity in cancer and regeneration.
    Laura D Attardi, Arati Rajeevan.
      Although p53 plays a vital role in tumor suppression, the molecular programs underlying its tumor suppressor function remain incompletely understood. Recent work coupling genetically engineered mouse models and single-cell RNA sequencing has illuminated new aspects of p53 function in governing cell state changes. During both lung adenocarcinoma suppression and lung injury repair, p53 acts in a plastic transitional cell state to drive alveolar type 1 cell differentiation, while p53 deficiency causes transitional cell persistence and cancer progression or tissue damage. New insights into p53 function in injury repair in other tissues have also emerged, including in injury-induced intestinal revival stem cells. These studies underscore the importance of p53 in specific plastic states, where it coordinately enforces differentiation and restrains lineage infidelity during tissue healing and cancer suppression.
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.004
  9. Cell. 2026 Mar 20. pii: S0092-8674(26)00234-5. [Epub ahead of print]
    Hyperinnervation inhibits organ-level regeneration in mammalian skin.
    Hannah T Tam, Jingyu Peng, Rebecca Freeman, Yulia Shwartz, Shlomi Brielle, Sakshi Garg, Siti Rahmayanti, Stephen J Crocker, Devin Coon, Ya-Chieh Hsu.
      Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration-restoring diverse cell types across lineages-remains rare. Here, we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular tissues with proper connectivity. However, this ability is lost soon after birth, resulting in failure to restore most cell types and hyperinnervation within the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered that three PWF-enriched genes-Timp1, Cxcl12, and Ccl7-inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation in postnatal wounds through the depletion of Cxcl12 in fibroblasts or nerve ablation enables regeneration of diverse lineages after injury. Our study identifies mechanisms that transition an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates that removing this barrier unlocks organ-level regeneration.
    Keywords:  Cxcl12; hyperinnervation; injury repair; nerve-tissue interactions; organ-level regeneration; regeneration; wound healing
    DOI:  https://doi.org/10.1016/j.cell.2026.02.027
  10. Nature. 2026 Mar 25.
    Remembrance of inflammations past.
    Chengxiang Qiu, Jay Shendure.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-00639-0
  11. bioRxiv. 2026 Mar 05. pii: 2026.03.03.709303. [Epub ahead of print]
    Toward Computationally Complete Spatial Omics.
    Wei Li, Liran Mao, Yunhe Liu, Fuduan Peng, Nadja Sachs, Wenrui Wu, Stephanie Pei Tung Yiu, Hanying Yan, Amelia Schroeder, Xiaokang Yu, Kaitian Jin, Shunzhou Jiang, Zihao Chen, Melanie L Loth, Lorena Gomez, Idania Lubo, Niklas Blank, Laith Z Samarah, Ankit Basak, Ye Won Cho, Chia-Yu Chen, David M Kim, Alex K Shalek, Luisa Maren Solis Soto, Joshua D Rabinowitz, Muredach P Reilly, Xuyu Qian, Christoph A Thaiss, Lars Maegdefessel, Linghua Wang, Humam Kadara, Sizun Jiang, Yanxiang Deng, Mingyao Li.
      Multimodal spatial omics has transformed biology by mapping molecular complexity within intact tissues, yet current technologies remain limited in the number of modalities measured simultaneously and often produce lower-quality data than single-modality assays. We present COSIE, a computational framework that generates high-resolution, multilayered molecular landscapes across tissue sections, individuals, and platforms. COSIE integrates histology, epigenome, transcriptome, proteome, and metabolome into a unified representation. Applied to 12 datasets spanning 10 spatial technologies, eight modalities, and nine tissue types, ranging from thousands of spots to millions of cells, COSIE outperforms existing methods. It resolves tissue structures, enhances noisy measurements, predicts unmeasured modalities, and captures dynamic processes. In human tumors, COSIE identifies invasive subregions linked to clinical outcomes and predicts spatial gene expression in TCGA samples using only histology images. By transforming fragmented data into comprehensive spatial maps, COSIE advances computationally complete spatial omics and the creation of digital tissue twins for biomedicine.
    DOI:  https://doi.org/10.64898/2026.03.03.709303
  12. bioRxiv. 2026 Mar 17. pii: 2026.03.13.711474. [Epub ahead of print]
    In vivo interrogation of transcriptional and epigenetic regulators of lung epithelial regeneration.
    Dawei Sun, Daisy Ann Hoagland, Daniel Strebinger, Chenlei Hu, Benno Orr, Shahinoor Begum, Giovanni Marrero, Jackson Weir, Ruth A Franklin, Fei Chen.
      Effective alveolar repair after viral lung injury requires precise coordination of alveolar type 2 cell (AT2) proliferation and differentiation to restore lung function. To uncover causal regulators of this process in the native tissue environment, we developed SAGE (Stable Adeno-Associated Virus Genomic IntEgration), an engineered AAV system that enables high-throughput in vivo genetic interrogation. SAGE supports both bulk phenotypic screening (SAGE-Perturb) and single-cell transcriptomic profiling (​​SAGE-Perturb-seq). Using this approach, we identified lysine acetyltransferase 8 (Kat8) as essential for epithelial repair following viral infection through the Non-Specific-Lethal (NSL) complex, and generated a time-resolved, high-resolution functional map of transcription factor knockouts during alveolar repair, revealing transcription factor dependences for distinct alveolar epithelial repair trajectories. This map further defined two independent AT2-derived transitional states: a reparative state, and a pathological state that is transcriptionally similar to the basaloid population observed in human pulmonary fibrosis. Disruption of transcription factors in the NF-𝜅B pathway prevented the emergence of the pathological transitional state, linking inflammation and maladaptive epithelial remodeling. SAGE represents a versatile platform for functional genomics in vivo, with applications extending across respiratory biology and disease.
    DOI:  https://doi.org/10.64898/2026.03.13.711474
  13. Nature. 2026 Mar;651(8107): 853-854
    AI scientists are changing research - institutions, funders and publishers must respond.
      
    Keywords:  Machine learning; Research data; Scientific community; Technology
    DOI:  https://doi.org/10.1038/d41586-026-00934-w
  14. Nature. 2026 Mar 25.
    How to build an AI scientist: first peer-reviewed paper spills the secrets.
    Davide Castelvecchi.
      
    Keywords:  Machine learning
    DOI:  https://doi.org/10.1038/d41586-026-00899-w
  15. Cancer Cell. 2026 Mar 26. pii: S1535-6108(26)00114-5. [Epub ahead of print]
    Immunometabolic gatekeeping: How tissue metabolism conditions tumor immunity.
    Naomi Iris van den Berg, Matouš Elphick, Kevin Mulder, Omar Bouricha, Omid Sadeghi-Alavijeh, Xiao Fu, Samra Turajlic.
      Why the link between immune infiltration and tumor control varies so strongly across tissues remains unresolved. We propose the "immunometabolic gatekeeping" framework, whereby tissue-intrinsic metabolic activity and waste-handling capacity shape anti-tumour immunity. In high-flux tissues, metabolic stress impairs immune surveillance, decoupling infiltration from control and allowing tumor outgrowth. This framework explains cancer paradoxes-including T cell prognostic heterogeneity, hereditary and pediatric tumor tropisms, sex-biased tumor incidence, and cancer-resistant species-and suggests metabolism-aware strategies for cancer prevention and immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.002
  16. Science. 2026 Mar 26. 391(6792): eadz6830
    Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
    Christopher J Cowley, Sairaj M Sajjath, Luis F Soto-Ugaldi, Mara Steiger, Samantha B Larsen, Thomas Carroll, Douglas Barrows, Alexandra Mattei, Kevin A U Gonzales, Wei Wang, Kevin Li, Alexander Meissner, Helene Kretzmer, Dana Pe'er, Elaine Fuchs.
      Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
    DOI:  https://doi.org/10.1126/science.adz6830
  17. Nat Rev Mol Cell Biol. 2026 Mar 27.
    Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target.
    A Doğa Yücel, Vadim N Gladyshev.
      Although epigenetic changes during ageing are well documented, we lack an integrated framework to systematically explain their mechanistic relationships. In this Review, we present a systems-level framework that demonstrates how epigenetic regulation controls ageing. We discuss four interdependent processes through which epigenetic fidelity - the capacity of chromatin regulatory systems to maintain precise gene expression states - progressively fails: deterioration of nuclear architecture, including breakdown of lamina-associated domains; dysregulation of epigenetic memory through chromatin-modifying complexes such as Polycomb repressive complex 2 (PRC2); nucleosome alterations involving replication-independent accumulation of the histone variant H3.3; and transcription reprogramming driven by transcription factors. These processes interact through cross-regulatory feedback, producing cascading failures in gene expression and cell-state maintenance. This framework reveals why therapeutics targeting epigenetic systems have consistent effects across multiple model systems and ageing phenotypes. The interconnected organization of chromatin regulation mechanisms creates concrete therapeutic targets to restore regulatory coherence. By providing mechanistic clarity on how epigenetic dysregulation drives ageing phenotypes, we aim to enable rational design of therapeutics that target the epigenetic systems that fail during ageing, rather than individual molecular defects.
    DOI:  https://doi.org/10.1038/s41580-026-00958-0
  18. bioRxiv. 2026 Mar 04. pii: 2026.03.02.706451. [Epub ahead of print]
    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.
    Clemens Hinterleitner, Valentin J A Barthet, Hailey V Goldberg, Kristen C Vogt, Ana Marie Perea, Stephen Ruiz, Logan R Hillger, Domhnall McHugh, Yu-Jui Ho, Almudena Chaves-Perez, Maria Skamagki, Sara Flowers, Natasha Rekhtman, Xueqian Zhuang, Gabriel Dessotti Barretto, Xiang Li, Jadae T Watson, Wei Luan, Janelle Simon, Tuomas Tammela, Rui Gardner, Charles M Rudin, Paul B Romesser, Matthew J Bott, Aveline Filliol, Daniel A Heller, Scott W Lowe.
      Fibrotic remodeling of tissues and tumors establishes immune-suppressive microenvironments that drive organ dysfunction and, in cancer, limit responses to immunotherapy. Cells exhibiting features of cellular senescence are conserved drivers of fibrotic remodeling and thus represent therapeutic targets, yet senescent states are heterogeneous and can exert both beneficial and pathogenic effects, complicating therapeutic intervention. Here, we show that P-selectin is selectively expressed by subsets of senescent-like cells in fibrotic tissues and fibrotic tumor microenvironments. Leveraging fucoidan-based nanoparticles that bind P-selectin, we develop senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated cell states. SMNPs exhibit potent antifibrotic and immunomodulatory activity while markedly improving therapeutic index. Mechanistically, we identify a pathogenic, immune-suppressive macrophage population as a principal functional target of SMNPs in vivo. In fibrotic tumors, niche remodeling restores immune infiltration and sensitizes tumors to immune checkpoint-based therapies. More broadly, SMNPs establish a generalizable nanotherapeutic strategy for selectively targeting pathogenic senescent cell subsets across fibrotic disease and cancer.
    DOI:  https://doi.org/10.64898/2026.03.02.706451
  19. Nat Rev Cancer. 2026 Mar 23.
    Striking the right balance with type I interferon signalling in cancer.
    Thomas B Chadwick, Joan So, Paul J Hertzog, Nicole M Haynes, Belinda S Parker.
      Type I interferons (IFNs), particularly IFNα and IFNβ, have an important role in cancer therapy, enhancing antitumour immunity and improving the efficacy of both conventional treatments and immunotherapies. However, despite considerable investment and research in IFN-based treatments, clinical success in solid malignancies has been hampered by toxicity and limited therapeutic efficacy. Recent studies show that type I IFNs can exert both immune-stimulatory and immune-suppressive effects within tumours, with their activity shaped by oncogenic signalling, chromatin state, the tumour microenvironment and therapeutic interventions. In this Review, we explore current insights into the regulation and function of type I IFNs in cancer, with a particular focus on tumour-intrinsic mechanisms controlling canonical and chronic signalling. We examine how these pathways influence immune surveillance, metastatic progression, therapeutic response and resistance. We also discuss how age-related changes, including immunosenescence and alterations in stromal composition and function, modulate type I IFN signalling and affect therapeutic outcomes. By dissecting the transcriptional, epigenetic and signalling mechanisms that control type I IFN responses, we outline actionable strategies to reprogramme IFN activity in tumours and ultimately improve response to therapies.
    DOI:  https://doi.org/10.1038/s41568-026-00915-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒27 at 7:57.