Weekly reading

Weekly Papers

A rolling archive of highlighted papers from PubMed and bioRxiv, grouped by topic but kept in each week’s original reading order.

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Week 25, 2026 · 15 Jun–21 Jun 2026

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Cell cycle

Mitotic phosphorylation of the microtubule nucleator γ-tubulin regulates spindle assembly.

Cdk1/cyclin B mediated phosphorylation of gamma-tubulin regulates spindle assembly.

Authors: Gefei Li, Khoi T D Le, Yi Duan, Robert Z Qi
Source: PubMed
Publication date: 13 June 2026
Primary category: Cell cycle
Priority: high
Abstract: The assembly of cellular microtubules relies heavily on γ-tubulin ring complex (γTuRC), a macromolecular assembly of γ-tubulin and associated proteins that serves as a nucleation template. Here, we identify that within γTuRC, γ-tubulin undergoes mitosis-specific phosphorylation at the conserved residue Ser364. This phosphorylation is mediated by Cdk1/cyclin B and occurs exclusively in cytoplasmic γTuRC, but not in γTuRC associated with mitotic spindles. Functionally, Ser364 phosphorylation strongly suppresses the microtubule-nucleating activity of γTuRC. Although γTuRC activity is essential for spindle microtubule assembly, disrupting Ser364 phosphorylation by expressing a non-phosphorylatable γ-tubulin mutant leads to defective spindle formation and chromosome segregation. Ser364 phosphorylation establishes spatial control over microtubule nucleation by inactivating cytoplasmic γTuRC, while spindle-associated γTuRC remains unphosphorylated and functionally active, consistent with the recently identified inhibitory control of spindle-localized Cdk1/cyclin B. This γTuRC regulation acts together with other Cdk1/cyclin B actions to eliminate non-spindle microtubules and support spindle assembly. Our findings reveal that Ser364 phosphorylation provides precise microtubule control for mitotic progression.

Epigenetic compartmentalization of mitotic chromosomes by phase-separation-driven repulsion between WDR5 and the chromosomal passenger complex.

WDR5 phase separation organizes mitotic chromosomes by repelling the CPC.

Authors: Yun Wang, Xianyun Jiang, Xing Liu, Xin Jiang, Xiyu Wang, Xiaoyu Song, Feng Chen, Yuanyuan Liu, Xu-Zhuo Gou, Ai-Hui Tang, Sibei Sheng, Xuebiao Yao, Zhonghuai Hou, Dan Liu
Source: PubMed
Publication date: 16 June 2026
Primary category: Cell cycle
Priority: high
Abstract: Histone modifications recruit chromatin regulators, but how their spatial patterns are established on mitotic chromosomes remains unclear. Spatial separation between active chromatin and centromeric signaling is essential for accurate chromosome segregation, yet the physical principles linking epigenetic marks to mitotic protein organization are poorly defined. Here, we show that liquid-liquid phase separation (LLPS) of WDR5, a core component of H3K4 methyltransferase complexes, acts as a spatial organizer of mitotic chromosomes. WDR5 LLPS is driven by multivalent charged and hydrophobic interactions in its N-terminal region. Phase-separated WDR5 repels the chromosomal passenger complex (CPC), segregating H3K4-trimethylated (H3K4me3) chromatin from H3T3-phosphorylated (H3T3ph) centromeric regions. Disrupting WDR5 condensation causes Aurora B mislocalization and chromosome misalignment, and restoring H3K4me3 alone does not rescue these defects. Computational modeling and rescue experiments support that WDR5-driven LLPS and histone modification signals cooperate to concentrate CPC at centromeres, revealing how LLPS and epigenetic information organize chromatin compartments during mitosis.

Novel KIF22 Variants Disrupt Mitosis in Human Chondrocytes and Expand SEMDJL2 Mechanisms.

KIF22 variants disrupt mitosis and chromosome segregation in human chondrocytes.

Authors: Amila Šemić, Kazette Yuen Yu Chan, Pricila Bernardi, Karina C Silveira, Cynthia Silveira, Denise P Cavalcanti, Peter Kannu, Jason Stumpff
Source: PubMed
Publication date: 17 June 2026
Primary category: Cell cycle
Priority: high
Abstract: Spondyloepimetaphyseal dysplasia with joint laxity, type 2 (SEMDJL2) is a rare skeletal disorder caused by pathogenic variants in KIF22, a mitotic chromokinesin that generates polar ejection forces (PEFs) to ensure proper chromosome alignment and segregation. Although SEMDJL2-associated variants disrupt chromosome segregation in epithelial cells, their effects in chondrocytes remain poorly understood. Here, we examined the functional consequences of the hotspot, dominant variant R149Q, a recently reported recessive variant R49Q, and two new dominant variants, P144T and E222Q, in human chondrocytes. Both novel variants were found in individuals with classic SEMDJL2 phenotypes. P144T and E222Q retained PEF-generating activity, whereas R49Q displayed reduced PEFs, consistent with their inheritance patterns. Live-cell imaging revealed that all variants perturbed mitosis. The heterozygous variants (P144T, E222Q, R149Q) dominantly impeded anaphase chromosome segregation and spindle pole separation, supporting classification as likely pathogenic. In contrast, R49Q produced milder, partially penetrant defects, consistent with reduced and dysregulated motor activity. These findings support a model that defines two mechanistic classes of KIF22 dysregulation: constitutive activation in heterozygous variants, which fail to inactivate KIF22 at anaphase onset, and mixed-state dysregulation in the recessive R49Q variant. This work broadens the mechanistic framework linking KIF22 variants to disrupted chondrocyte mitosis and SEMDJL2. [Media: see text] [Media: see text] [Media: see text].

SIRT2 antagonizes MOF function during mitotic entry.

The study identifies antagonism between SIRT2 and MOF during G2-M transition and mitotic progression.

Authors: María Espinosa-Alcantud, Núria Sima, Irene Fernández-Duran, Anna Marazuela-Duque, Gerard Martínez-Cebrián, Anna Guitart-Solanes, Andrés Gámez-García, Paloma Martínez-Redondo, Laia Bosch-Presegué, Berta N Vazquez, Luis Paños, Joan Josep Bech, Tim Thomas, Marian A Martinez-Balbás, Anne K Voss, Marcus Krüger, Lourdes Serrano, Mireia Olivella, Sergi Cuartero, Carolina de la Torre, Alejandro Vaquero
Source: PubMed
Publication date: 19 June 2026
Primary category: Cell cycle
Priority: high
Abstract: Mitosis entry is tightly regulated by a complex network of mechanisms involving epigenetic modifications, signaling pathways, transcriptional control, and structural changes. Although substantial progress has been made in understanding these processes individually, the mechanisms integrating chromatin dynamics with mitotic regulators are still not fully understood. Here, we identify a functional antagonism between the deacetylase SIRT2 and the acetyltransferase MOF in the G2-M transition and mitotic progression. This interplay, which involves MOF deacetylation by SIRT2, regulates key histone marks, including H4K16ac (histone 4 lysine-16 acetylation) deacetylation and H4K20me1 (histone 4 lysine-20 monomethylation) deposition, condensin II loading, and the stability of the key mitotic regulator PLK1, and contributes to the FOXM1-mediated transcriptional control of mitosis. Our findings reveal a previously unrecognized layer of regulation in G2-M progression with possible impact in cancer, highlighting the intricate cross-talk between chromatin dynamics and mitotic control and providing important insights into chromosomal stability.

Mitotic Cdc42 waves encode PI(3,4)P2 signaling and Golgi morphological state to control spindle scaling.

Investigates how mitotic Cdc42 waves, regulated by PI(3,4)P2 turnover and INPP4B, control mitotic spindle scaling.

Authors: Suet Yin Sarah Fung, Shengping Xiao, Yujin Bao, Morven Graham, Maohan Su, Xinran Liu, Joerg Bewersdorf, Min Wu
Source: PubMed
Publication date: 19 June 2026
Primary category: Cell cycle
Priority: high
Abstract: Self-organizing waves are observed in numerous biological systems and may encode spatial and temporal information for cellular organization in the absence of prepatterns. In mitotic mast cells, periodic cortical waves emerge before spindle assembly with wave periods that are proportional to cell size. Here, we investigate the mechanisms that govern cortical wave scaling and examine the consequence of wave perturbation on mitotic spindle size scaling. We find that the periods of mitotic waves are regulated by the turnover of phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] on the plasma membrane, which depends on inositol polyphosphate-4-phosphatase type II (INPP4B). Genetic depletion of INPP4B increases cortical wave period and spindle length. Intriguingly, we observed mitotic wave periods that tunes continuously during mitosis, indicating the existence of a fast, posttranslational regulatory mechanism for wave scaling. We further find that the regulation of mitotic waves on the plasma membrane is controlled by the sequestering of INPP4B and PI(3,4)P2 upon mitotic Golgi fragmentation. On the basis of these findings, we propose a cell size-sensing mechanism in which cortical waves act like sonar waves, adjusting their timing and propagation based on the shuttling of signaling proteins between the cell cortex and intracellular organelles. This rapid communication scheme allows the cell to adjust spindle scaling dynamically, ensuring accurate cell division.

Architecture and function of holocentric CENP-A-independent inner kinetochores.

The paper describes the structure and function of holocentric kinetochores in Bombyx mori, focusing on chromosome-wide centromeric activity.

Authors: Christine Yu, Sundar Ram Sankaranarayanan, Gaetan Cornilleau, Anna C Howes, Caleigh M Azumaya, Eric S Day, Inna Zilberleyb, Bobby Brillantes, Tommy K Cheung, Leonie Dec, Damarys Loew, Phong Tran, Christopher M Rose, Ines Anna Drinnenberg, Claudio Ciferri, Stanislau Yatskevich
Source: PubMed
Publication date: 19 June 2026
Primary category: Cell cycle
Priority: high
Abstract: Kinetochores are essential macromolecular complexes anchoring chromosomes to the mitotic spindle, ensuring faithful cell division. Despite their critical role, the structural organization of kinetochores across diverse species remains poorly understood. We present the inner kinetochore constitutive centromere-associated network (CCAN) structure of the silkmoth Bombyx mori, an insect that lacks the canonical centromere-specifying histone variant CENP-A and exhibits chromosome-wide centromeric activity (holocentric). The B. mori CCAN incorporates four previously uncharacterized centromeric subunit proteins that are structurally related to the Dam1/DASH complex but function in scaffolding the inner kinetochore rather than in microtubule binding. Similar to the yeast and human systems, the B. mori CCAN also entraps DNA within its central closed chamber. However, unlike these systems, the B. mori CCAN can also assemble in vitro into a self-contained head-to-head dimer via atypical histone-fold protein dimerization. On the basis of our findings, we propose that the holocentric organization may emerge from the modular arrangement of discrete kinetochore units.

Genome stability

TASP1-mediated cleavage of REV3L enhances the activity of DNA polymerase ζ in mammalian cells.

Discusses Pol-zeta activity and ATR-dependent phosphorylation in response to replication stress.

Authors: Jordane Goulas, Basile Guignier, Barbara Ben Yamin, Caroline Pouvelle, Andrey Yurchenko, Emmanuelle Despras, Luciana de Oliveira, Pierre Laplante, Dorian Bochaton, Damien Plassard, Wei Yang, François-Xavier Theillet, Xavier Veaute, Richard D Wood, Sergey Nikolaev, Agnès M Cordonnier, Patricia L Kannouche
Source: PubMed
Publication date: 15 June 2026
Primary category: Genome stability
Priority: high
Abstract: DNA polymerase ζ (Polζ) is essential for replication across damaged DNA, yet the mechanisms governing its regulation in mammalian cells remain incompletely understood. The catalytic subunit REV3L is nearly twice the size of its yeast counterpart owing to a large vertebrate-specific insertion, and recent studies reported that REV3L undergoes proteolytic cleavage by the endopeptidase TASP1. Here, we show that REV3L cleavage generates two stable fragments, Nter-p70 and Cter-p300, which reassociate into a long-lived heterodimeric complex with enhanced polymerase activity. This interaction is stabilized by key residues within the catalytically inactive EXO domain. The cleaved Polζ complex associates with chromatin, binds nascent DNA, and undergoes ATR-dependent phosphorylation in response to replication stress. Importantly, preventing REV3L cleavage markedly impairs Polζ activity, reduces cisplatin-induced mutagenesis, and increases RAD51 nuclear foci and sister chromatid exchange, consistent with a compensatory shift toward homologous recombination-mediated repair. Together, our findings suggest that the vertebrate-specific expansion of REV3L necessitated cleavage to restore structural organization and optimize catalytic function, representing an evolutionary adaptation in DNA damage tolerance pathways.

Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining.

Discovery of UFM1 receptors regulating non-homologous end-joining (NHEJ) in DNA repair.

Authors: Zijuan Wang, Benjamin M Foster, Isabelle C da Costa, Yue Wu, Deepak Behera, Francesca Conte, Eleanor W Trotter, Felicia Wednesday Lopezcolorado, Maria Jose Cabello-Lobato, Shweta Choudhary, Reuven Wiener, Petra Beli, Duncan L Smith, William H Banks, Steven Bagley, Shane McKee, Meenakshi Minnis, Stefan Meyer, Amanda K Chaplin, Wolfgang Dörner, Henning D Mootz, Iain M Hagan, Yaron Galanty, Jeremy M Stark, Igor Larrosa, Matthew J Cliff, Christine K Schmidt
Source: PubMed
Publication date: 15 June 2026
Primary category: Genome stability
Priority: high
Abstract: Posttranslational modifications with ubiquitin-like modifiers (UBLs) are critical for genome maintenance, yet many remain mechanistically uncharacterised. Here, we identify UFM1 as a key regulator of non-homologous end-joining (NHEJ), a major DNA double-strand break repair pathway. Using a structure-guided chemical biology approach, we develop a photo-crosslinkable UFM1 probe and, in combination with NMR, map non-canonical UFM1-binding interfaces in core NHEJ factors, including the disordered XRCC4 tail. Mechanistically, proximity-dependent proteomics and functional assays identify Ku70 as a crucial UFMylation substrate and reveal a UFM1-dependent axis in which XRCC4 engages UFMylated Ku70 to stabilise NHEJ complex assembly on chromatin. Disruption of this molecular mechanism via UFSP2 depletion or a hypomorphic UBA5 variant in patient-derived cells impairs NHEJ function, linking UFMylation defects to compromised genome integrity processes. Our findings define a complete UFM1 signalling module in DNA repair and establish a generalisable framework for dissecting low-affinity UBL networks with broad functional and disease relevance.

Amphiregulin drives EGFR-dependent genome stability in colorectal cancer and represents a targetable vulnerability.

Amphiregulin modulates EGFR-dependent DNA replication and repair in colorectal cancer.

Authors: Sun-Ji Park, Sung-Woo Lee, Heegyum Moon, Su-Min Jung, Jin-Man Kim, Dong-Seok Lee, Eui-Hwan Choi
Source: PubMed
Publication date: 15 June 2026
Primary category: Genome stability
Priority: high
Abstract: Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistochemistry and western blot revealed high expression of AREG in CRC tumors compared to other CRCs. Our findings indicate that AREG translocates into the nucleus, a process potentially facilitated by the inhibition of endocytosis. Transcriptomic analyses suggest an association between AREG expression and genes regulating EGFR signaling, replication fork dynamics, and homologous recombination. Depletion of AREG via siRNA or CRISPR-Cas9 led to S/G₂ arrest, replication tract shortening, and increased RAD51, RPA, and γH2AX foci, resulting in a 40-60% reduction in proliferation effects that were not fully recapitulated by small-molecule EGFR inhibitors. In xenograft models, AREG knockout reduced tumor growth and suppressed the phosphorylation of EGFR, ERK, STAT3, and BRAF. Furthermore, combining AREG loss with EGFR inhibition appeared to enhance antitumor effects. These findings suggest that AREG may function as a mediator of EGFR signaling and genome maintenance in CRC.

FANCA-dependent FEN1 recruitment suppresses transcription-replication conflicts and PARPi sensitivity.

FANCA deficiency disrupts FEN1 recruitment leading to genomic instability and PARPi sensitivity.

Authors: Qinhong Wang, Simon W Ellington, Paolo Guerra, Faeze Gharibpoor, Dennis A Simpson, Min-Guk Cho, Adriana Beltran, Gaorav P Gupta
Source: PubMed
Publication date: 16 June 2026
Primary category: Genome stability
Priority: high
Abstract: Synthetic lethality (SL) underlies the success of PARP1 inhibitors (PARPi) in treating homologous recombination (HR)-deficient cancers, yet their broader applicability beyond HR deficiency remains poorly defined. Here, we performed an in vivo CRISPR screen that identifies FANCA deficiency as a driver of tumor progression and PARPi SL, validated across diverse human cancer models. Notably, FANCA loss does not impair HR but instead disrupts FEN1 recruitment to replication forks, leading to defective Okazaki fragment maturation, lagging-strand single-strand DNA gap accumulation, and RPA exhaustion upon PARPi treatment. Additionally, FANCA loss in oncogene-expressing cells promotes transcription-replication conflict (TRC) accumulation selectively on the lagging strand and sensitizes HR-proficient cells to PARPi, a phenotype reversible by RNA polymerase II inhibition or RNase H overexpression. Together, these findings identify FANCA deficiency as a context-specific PARPi vulnerability and establish FANCA as a key suppressor of TRCs required for genomic stability under oncogenic replication stress.

ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.

ZNF512B suppresses SASP and maintains genome integrity via DNA repair.

Authors: Sanjeeb Kumar Sahu, Sebastian Memczak, Sudhir Thakurela, Jinlong Lu, Priya Gupta, Naresh Mutukula, Alex Hirano, Yingzi Zhang, Tomoaki Hishida, Masakazu Kurita, Chao Wang, Yanjiao Shao, April Williams, Max Shokhirev, Vijay K Tiwari, Concepcion Rodriguez Esteban, Pradeep Reddy, Alexander Meissner, Mo Li, Juan Carlos Izpisua Belmonte
Source: PubMed
Publication date: 16 June 2026
Primary category: Genome stability
Priority: high
Abstract: Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.

Confined migration induces non-lethal DNA damage in developing neurons.

Demonstrates that confined neuronal migration induces DNA double-stranded breaks (DSBs) due to mechanostress.

Authors: Zhejing Zhang, Andres Canela, Junko Kurisu, Peilin Zou, Takumi Kawaue, Naotaka Nakazawa, Noriko Takeda, Mai Saeki, Masaki Utsunomiya, Merve Bilgic, Fumiyoshi Ishidate, Gianluca Grenci, Takahiro Furuta, Yusuke Kishi, Hiroyuki Sasanuma, Mineko Kengaku
Source: PubMed
Publication date: 17 June 2026
Primary category: Genome stability
Priority: high
Abstract: Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear-envelope rupture and DNA damage in cancer cells, which may contribute to malignant transformation during tumour progression3-6. However, the importance of DNA damage in physiological migration is less well understood. Here we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-stranded breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. In contrast to many other migratory cells, these DSBs occur without detectable nuclear envelope rupture. Confined migration increases topoisomerase-IIβ covalently bound DSBs, and these lesions are repaired through non-homologous end-joining during brain development without causing cell death. Genome sequencing revealed that DSBs tend to occur at transcriptionally inactive regions. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.

Towards a unified model of aneuploid karyotype dynamics.

Modeling aneuploid karyotype dynamics and chromosomal segregation errors.

Authors: Mathieu Hénault, Lisa M Wood, Lydia R Heasley
Source: PubMed
Publication date: 18 June 2026
Primary category: Genome stability
Priority: high
Abstract: Aneuploidies-whole-chromosome copy number imbalances arising from nondisjunction-underlie numerous congenital and somatic disorders, but unlike many other disease-causing variants, they can revert back to euploidy through subsequent errors of the same type. The extent to which this inherent plasticity impacts the stability and persistence of aneuploid karyotypes in populations remains poorly understood, a gap in knowledge that continues to limit our understanding of aneuploidy-driven disease incidence, penetrance, and progression. To assess how reversion shapes aneuploid population dynamics, we developed a budding yeast system to systematically measure the rates at which aneuploidies arise and revert and quantify the relative fitness differences between these karyotypic states. We integrated these data into a computational framework encompassing the broad physiological range of aneuploid karyotype dynamics captured in our experiments. The resulting models reveal that canonical reversion (i.e., subsequent secondary nondisjunction) occurs rarely, conferring a negligible effect on the population dynamics of most chromosomal aneuploidies. However, our models also identified that the reversion dynamics of some chromosomes-those displaying extremely high apparent rates of reversion-were more consistent with a coupled mutational process involving a transient aneuploid state. Whole-genome sequencing and live-cell microscopy demonstrates that this mechanism is facilitated by unresolved intermolecular linkages that disrupt chromosome segregation, leading to chromosome breakage and recombination-mediated repair over subsequent cell divisions. Collectively, this work advances a model of aneuploid population genetics and expands our perspective of the diverse, and chromosome-specific, mutational mechanisms shaping genome architecture.

MCM2 germline variants predispose to familial papillary thyroid carcinoma due to genomic instability caused by MCM complex disruption.

Identifies MCM2 germline variants that cause genomic instability and familial papillary thyroid carcinoma.

Authors: Shiyu Cao, Tengyun Ma, Long Zhao, Lin Xiao, Peichuan Zhang, Yuze Han, Yichen Liu, Yong Jiang, Feng Ye
Source: PubMed
Publication date: 18 June 2026
Primary category: Genome stability
Priority: high
Abstract: In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three MCM2 gene mutations (c.1092 C > G, p.N364K; c.1975A>G, p.I659V; and c. 2379 G > A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of MCM2 with its partner proteins (MCM3-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, γ-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in MCM2-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that MCM2-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in MCM2-deficient tumors. In our study, based on the fPTC cohort, germline variants of MCM2 predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. MCM2 deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify MCM2 as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of MCM2 testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.

SCP4 dephosphorylates mitotic histone H3 to maintain chromosome stability.

SCP4 dephosphorylates mitotic histone H3 (H3T3) to maintain chromosome stability.

Authors: Yupiao Zheng, Zhengmao Zhang, Qi Wang, Jin Cao, Yang Li, Tingbo Liang, Xin-Hua Feng, Xia Lin
Source: PubMed
Publication date: 19 June 2026
Primary category: Genome stability
Priority: high
Abstract: Mitosis is tightly regulated at multiple levels to ensure chromosome stability. The transient phosphorylation of histone H3 at Threonine 3 (H3T3) during cell division is critical for proper chromosome condensation and the accurate segregation of sister chromatids. While Haspin has been identified as the kinase responsible for H3T3 phosphorylation during mitosis, the phosphatases that counteract this modification to maintain balanced phosphorylation levels remain under investigation. In this study, we systematically screened phosphatases encoded in the human genome and identified the nuclear phosphatase SCP4 as an H3T3 phosphatase. SCP4 modulates H3T3 phosphorylation levels and influences the chromosomal recruitment of chromosomal passenger complex (CPC) during mitosis. Aberrant SCP4 expression leads to defective chromosome separation during metaphase and chromosome lagging in anaphase, resulting in aneuploidy. Notably, in SCP4 knockout mice, zygotes exhibit mitotic defects during the first cleavage at the two-cell stage, highlighting SCP4's essential role in ensuring faithful cell division. In summary, we identify SCP4 as a novel phosphatase regulating H3T3 phosphorylation and chromosome dynamics during mitosis, providing new insights into mechanisms safeguarding genomic stability.

Replication origin firing capacity indicates ATR inhibitor sensitivity.

Links replication origin firing capacity to ATR inhibitor sensitivity in cancer cells.

Authors: A Lumeau, P L Pfuderer, J A Scarth, E Maniati, M A Guscott, N Shaikh, F B Copley, H Gerdes, S De Angelis, E L Alard, J Wang, P R Cutillas, F K Mardakheh, M A Boemo, J V Forment, S E McClelland
Source: PubMed
Publication date: 19 June 2026
Primary category: Genome stability
Priority: high
Abstract: Inhibitors of ATR, a central kinase controlling DNA replication origin firing and cellular checkpoints, are undergoing clinical trials, yet mechanisms underpinning sensitivity to ATR inhibitors (ATRi) and patient stratification biomarkers are lacking. Here, we perform in parallel, proteomics, transcriptomics and functional analyses and demonstrate that sensitive cancer cell lines have higher expression of DNA replication initiation factors, and exhibit higher origin firing, increased pan-nuclear γH2AX signals and cell death upon ATRi treatment. ATRi sensitivity is causally associated with origin firing rates, since we could modulate ATRi sensitivity by either up- or down-regulating origin firing capacity using CDC7 inhibition, CDK2 inhibition or CDC45 overexpression in both breast and colorectal cancer cells. High expression of replication initiation factors predicts ATRi sensitivity across cell lines from multiple cancer types and acute myeloid leukemia patient samples. This study reveals a contribution of lethal origin firing capacity to ATR sensitivity, providing key steps towards developing a multimodal clinically applicable biomarker.

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.

ATF4 coordinates metabolic and translational programs to regulate DNA replication timing in leukemia.

Authors: Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes
Source: PubMed
Publication date: 20 June 2026
Primary category: Genome stability
Priority: high
Abstract: Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.

Cancer biology

A toxic STING-SAMHD1 axis drives replication stress in progeria and cancer cells.

Defines a STING-SAMHD1 axis that drives replication stress and genome instability in progeria and cancer.

Authors: Barbara Teodoro-Castro, Rafael Cancado de Faria, Elena V Shashkova, Atika Malique, Madison B Adolph, Lilian N D Silva, Susana Gonzalo
Source: PubMed
Publication date: 8 June 2026
Primary category: Cancer biology
Priority: high
Abstract: STING is an innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce interferon signaling. Recent studies reveal that STING participates in non-canonical signaling pathways and localizes to the nucleus, where its functions remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of the lamin-A mutant protein 'progerin', STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress is a trigger of STING nuclear accumulation and chromatin binding. In addition, we uncover that STING binds to nascent DNA and promotes replication stress in progeria and tumor cells. Mechanistically, STING causes replication fork slowing and stalling by limiting dNTPs availability. Upon fork stalling, STING hinders replication fork protection/stability by facilitating MRE11-mediated nascent DNA degradation (NDD). Importantly, STING's contribution to dNTP depletion and NDD is mediated by SAMHD1. Depletion of SAMHD1 phenocopies STING abrogation in reducing replication stress in progeria cells, and rescues replication fork speed and stability in STING-expressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives replication stress and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.

The DBD-α4 helix of EWSR1::FLI1 is required for GGAA microsatellite binding that underlies genome regulation in Ewing sarcoma.

Identifies role of EWSR1::FLI1 DBD-alpha4 helix in GGAA microsatellite binding in Ewing sarcoma.

Authors: Ariunaa Bayanjargal, Cenny Taslim, Iftekhar A Showpnil, Julia Selich-Anderson, Jesse C Crow, Runwei Zhou, Stephen L Lessnick, Emily Rose Theisen
Source: PubMed
Publication date: 15 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Ewing sarcoma is the second most common bone cancer in children and young adults. In 85% of patients, a translocation between chromosomes 11 and 22 results in a potent fusion oncoprotein, EWSR1::FLI1. EWSR1::FLI1 is the only genetic alteration in an otherwise unaltered genome of Ewing sarcoma tumors. The EWSR1 portion of the protein is an intrinsically disordered domain involved in transcriptional regulation by EWSR1::FLI1. The FLI portion of the fusion contains a DNA binding domain shown to bind core GGAA motifs and GGAA repeats. A small alpha-helix in the DNA binding domain of FLI1, DBD-α4 helix, is critical for the transcription function of EWSR1::FLI1. In this study, we aimed to understand the mechanism by which the DBD-α4 helix promotes transcription and therefore oncogenic transformation. We utilized a multi-omics approach to assess chromatin organization, active chromatin marks, genome binding, and gene expression in cells expressing EWSR1::FLI1 constructs with and without the DBD-α4 helix. Our studies revealed DBD-α4 helix is crucial for cooperative binding of EWSR1::FLI1 at GGAA microsatellites. This binding underlies many aspects of genome regulation by EWSR1::FLI1, such as formation of topologically associated domains (TADs), chromatin loops, enhancers, and productive transcription hubs.

Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.

KRAS-driven interferon signaling primes pancreatic cancer for necroptosis via MLKL.

Authors: Sofya Tishina, Alina Dahlhaus, Marta Manik, Lejla Mulalic, Janine Murr, Michael Kotliar, Hassan Rakhsh-Khorshid, Myrto Kostopoulou, Florian Hocher, Jenny Stroh, Julia Beck, Riley M Williams, Gülce G Balta, Fanyu Liu, Ali T Abdallah, Christina M Bebber, Moritz Reese, Jonathan K M Lim, Alexander Quaas, Johannes Brägelmann, Manolis Pasparakis, Filippo Beleggia, Siddharth Balachandran, Anna Trauzold, Gianmaria Liccardi, Igor Astsaturov, Maximilian Reichert, Ariadne Androulidaki, Silvia von Karstedt
Source: PubMed
Publication date: 15 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.

SMARCA4 loss reprograms p300 chromatin occupancy to subvert p53-mediated transcriptional repression in ovarian small cell carcinoma.

Discusses SMARCA4 loss and p300 reprogramming to subvert p53-mediated repression in ovarian cancer.

Authors: Giulio Aceto, Kexin Liu, Azadeh Arabzadeh, Shuhe Tsai, Yibo Xue, Anie Monast, Virginie Pilon, Mengke Han, Geneviève Morin, Kitty Pavlakis, Lili Fu, Morag Park, William D Foulkes, Yemin Wang, Sidong Huang
Source: PubMed
Publication date: 15 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer driven by biallelic inactivation of SMARCA4 (BRG1), the ATPase subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. Despite its aggressiveness, SCCOHT exhibits a low mutation burden and retains wild-type p53 tumor suppressor. Using an integrative omics approach, we show that SMARCA4 loss redistributes the p300 acetyltransferase to promoters of cell cycle progression genes, increasing histone H3 lysine 27 acetylation (H3K27ac) and promoting transcription that sustains tumor growth. This opposes p53-mediated transcriptional repression at these loci, where co-occupancy of p53 and histone deacetylase HDAC2 are associated with decreased H3K27ac and suppressed gene expression. SMARCA4 restoration or pharmacologic inhibition of p300 suppresses SCCOHT growth, an effect reversed by p53 deletion and accompanied by reactivation of these cell cycle progression genes. Our findings uncover a chromatin-based mechanism whereby SMARCA4 loss subverts p53-mediated transcriptional repression through reprogramming p300 genomic occupancy to sustain oncogenic growth, highlighting p300 as a potential therapeutic target in SCCOHT.

Cathepsin L deletion enhances sensitivity to anticancer drugs through Parkin-mediated ubiquitination of Bcl-xL and USP53-induced Survivin destabilization.

Cathepsin L deletion sensitizes RCC cells to anticancer drugs via Parkin-mediated ubiquitination of Bcl-xL and USP53.

Authors: Seung Un Seo, Seon Min Woo, Yongsoo Kwon, Shin Kim, Hyun-Shik Lee, Sang Hyun Kim, Kyoung-Jin Min, Simmyung Yook, Taeg Kyu Kwon
Source: PubMed
Publication date: 15 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Cathepsin L (Cat L), a lysosomal endopeptidase, is overexpressed in human renal clear carcinoma (RCC); however, its impact on apoptosis remains unclear. Results revealed that inhibition (SID, a specific inhibitor), knockdown (siRNA), or knockout of Cat L sensitizes human carcinoma cells to anticancer drugs-mediated apoptosis through the downregulation of Bcl-xL and Survivin at the post-translational level. Moreover, combined treatment with SID and sorafenib reduced the tumor growth in a xenograft model. Deletion of Cat L induced Parkin stabilization by increasing DUB3 expression at the transcriptional level. Parkin knockdown significantly prevented SID-induced Bcl-xL downregulation. Conversely, ectopic expression of Parkin suppressed Bcl-xL expression. Furthermore, SID-mediated Parkin upregulation inhibited USP53 deubiquitinase protein expression, leading to the degradation of Survivin expression through its ubiquitination. Parkin directly ubiquitinated Bcl-xL and USP53, but not Survivin. These results demonstrate that inhibition of Cat L enhances anticancer drugs-induced apoptosis through Parkin-mediated ubiquitination of Bcl-xL and USP53. Moreover, the downregulation of USP53 suppressed the expression of Survivin. Therefore, Cat L can be considered a potential candidate molecular target for the treatment of RCC.

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.

Integrated stress response (ISR) drives lineage reprogramming and cancer evolution in lung adenocarcinoma.

Authors: Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas
Source: PubMed
Publication date: 15 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.

KPT-330-mediated XPO1 inhibition impairs homologous recombination and enhances radiosensitivity in extranodal NK/T-cell lymphoma.

XPO1 inhibition via KPT-330 enhances radiosensitivity in NK/T-cell lymphoma by impairing HR.

Authors: Huijie Zhou, Qiuluo Liu, Kexing Ren, Qian Luo, Chunli Yang, Tian Fang, Xi Chen, Liqun Zou
Source: PubMed
Publication date: 16 June 2026
Primary category: Cancer biology
Priority: high
Abstract: BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting. METHODS: We analysed XPO1 expression in ENKTL and assessed its role in radiosensitization using monoallelic XPO1-knockout models and KPT-330 in vitro and in xenografts. Mechanistic studies focused on the c-Myc-RAD51/CHEK1 axis, and clinical efficacy was evaluated in two R/R patients. RESULTS: Immunohistochemistry showed XPO1 overexpression in primary treatment-naïve ENKTL specimens relative to nasal polyp controls, and high XPO1 expression was associated with inferior overall survival. Monoallelic XPO1 knockout impaired homologous recombination (HR) repair, establishing a DNA repair defect exploitable as a radiosensitizing vulnerability. Pharmacologic inhibition of XPO1 with KPT-330 recapitulated these HR defects and synergised with radiotherapy. Mechanistically, KPT-330 disrupts the XPO1-c-Myc-RAD51/CHEK1 axis by blocking c-Myc nuclear export, reducing c-Myc abundance and promoter occupancy at the RAD51 and CHEK1 loci, thereby impairing HR. In two heavily pretreated R/R ENKTL patients, radiotherapy rechallenge plus low-dose KPT-330 achieved one partial response and one complete response with manageable toxicity. CONCLUSIONS: XPO1 inhibition impairs HR and enhances radiosensitivity by disrupting the c-Myc-RAD51/CHEK1 axis. These findings support prospective evaluation of KPT-330-based radiosensitization in R/R ENKTL.

Clinicogenomic analysis of EGFR-mutant lung tumors identifies Rb pathway inactivation as a hallmark of squamous transformation.

Identifies Rb pathway inactivation and CDKN2A/B deletions as drivers of squamous transformation in EGFR-mutant lung tumors.

Authors: Alexandria Dymun, Mark Y Jeng, Arielle Elkrief, Harshita Mehrotra, Soo-Ryum Yang, Christina Wilson, Natasha Rekhtman, Irina Linkov, Amanda Pupo, Christina Falcon, Clare J Wilhelm, Parvathy Manoj, Hong Zhong, Harsha Sridhar, Mark G Kris, Nicholas D Socci, Juan Qiu, Elisa de Stanchina, Allison L Richards, Mark T A Donoghue, Charles M Rudin, Helena A Yu, Álvaro Quintanal-Villalonga
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Histologic transformation to lung squamous cell carcinoma (LUSC) is an underrecognized mechanism of resistance in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD). Although AKT and MYC activation have been linked to LUSC features, the clinicogenomic determinants of this transformation remain undefined. In this study, we performed comprehensive clinical and multiomic profiling-including genomic, transcriptomic, methylation, and proteomic analyses-of EGFR-mutant tumors that were transforming, adenosquamous (LUAS), or de novo LUSC. Patients with EGFR-mutant LUSC or LUAS had shorter overall survival on first-line osimertinib compared with those with EGFR-mutant LUAD. Transforming tumors were enriched for alterations in the retinoblastoma (Rb) and AKT pathways, particularly cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions. These alterations were also frequent in EGFR-wild-type LUSC and associated with shorter time-to-osimertinib discontinuation. In genetically engineered human in vivo models, Rb inactivation, in combination with AKT and MYC activation, enhanced the acquisition of LUSC features. Single-cell RNA profiling of such models recapitulated the molecular changes observed in the transforming clinical specimens and identified MET pathway up-regulation during transformation. Combined EGFR and MET inhibition suppressed tumor growth in patient-derived xenograft models of LUSC transformation. Together, these findings highlight Rb pathway inactivation as a promoter of LUSC transformation in EGFR-mutant lung cancer and identify MET signaling as a therapeutic vulnerability that may suppress plasticity in this setting and extend response to targeted therapy.

Mtg16/Eto2 tumor suppressor maintains and establishes repression by distinct mechanisms.

Mtg16 tumor suppressor mechanism involving transcriptional repression and HDAC requirement.

Authors: Anna E Gilbert, Monica L Bomber, Jacob D Ellis, Luke N Bartlett, Joyeeta Chakraborty, Andrew W Folkmann, Kristy R Stengel, Scott W Hiebert
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: The myeloid translocation gene (Mtg) family of transcriptional corepressors is a frequent target of chromosomal translocations and deletions in cancer, yet the mechanisms underlying tumor suppression and transcriptional repression are unclear. We employed a chemical-genetic system that enabled rapid degradation and recovery of Mtg16 to study both the maintenance and re-establishment of transcriptional repression. Nascent transcription and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses showed that Mtg16 repressed highly accessible promoters and enhancers, including Lmo2, Myb, and Gfi1b. The highest confidence targets included these oncogenes, which were transcribed at low levels in the presence of Mtg16 and re-repressed upon its recovery. Proximity ligation assays showed that HEB associated with p300 in the absence of Mtg16, but endogenous levels of Mtg16 impaired this association. Repression was associated with decreased H3K27ac, but loss of H3K27ac also occurred at non-repressed sites. Strikingly, HDAC inhibition had little effect on the maintenance of repression but strongly impaired re-repression following Mtg16 restoration, revealing a selective requirement for HDACs during repression onset.

Becotatug Vedotin for Recurrent/Metastatic Nasopharyngeal Carcinoma (Magic-M001): A Multicenter, Randomized Trial.

Randomized trial of becotatug vedotin for recurrent/metastatic nasopharyngeal carcinoma.

Authors: F Han, Y Q Xiang, X H Wang, S Qu, L Q Tang, X L Shu, P Zhang, S F Qiu, Y J Zhou, Y Guo, G Q Xu, Q Li, K Y Yang, Y Q Du, M J Xu, J G Li, F Wang, S T Huang, Y J Huang, H Wu, X Z Chen, Y Wei, W L Wu, S M Pan, H M Lin, S W Xiao, Y W Dou, R Dai, P Zhang, Y S Jin, R H Xu
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: BACKGROUND: Patients with recurrent/metastatic nasopharyngeal carcinoma (NPC) had limited treatment option and dismal prognosis after failure to programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors and chemotherapy. METHODS: This multicenter, open-label, randomized trial investigated anti-epidermal growth factor receptor antibody-drug conjugate becotatug vedotin in patients with recurrent/metastatic NPC after failure to ≥2 lines of systemic therapies, including chemotherapy and PD-1/PD-L1 inhibitors. Eligible participants were randomized 1:1 to receive becotatug vedotin 2.3 mg/kg every 3 weeks or chemotherapy (capecitabine or docetaxel). The co-primary endpoints were the independent review committee-confirmed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Between April 6, 2023, and December 27, 2023, a total of 173 patients were randomized, with 86 assigned to becotatug vedotin and 87 to chemotherapy. As of June 30, 2024, the ORR was significantly higher with becotatug vedotin than with chemotherapy (30.2% vs 11.5%; P = 0.003). With a median follow-up of 7.39 months, becotatug vedotin was associated with a significantly reduced risk of disease progression or death compared with chemotherapy (median PFS, 5.82 vs 2.83 months; hazard ratio, 0.63; 95% CI, 0.43-0.91; log-rank P = 0.01). As of December 30, 2024, the interim OS analysis showed a median OS of 17.08 months with becotatug vedotin and 11.99 months with chemotherapy (hazard ratio, 0.73; 95% CI, 0.48-1.12; log-rank P = 0.15), with a median follow-up of 13.47 months. The safety profiles were comparable between treatment groups. CONCLUSIONS: Among patients with heavily pretreated and immunotherapy-exposed recurrent or metastatic NPC, becotatug vedotin significantly improved ORR and PFS compared with chemotherapy, with comparable toxicity and encouraging but immature OS results.

Exhausted CD8⁺ T cells promote ovarian cancer immunosuppression via CCL3-Driven M2 macrophage polarization.

Shows exhausted CD8+ T cells promote ovarian cancer immunosuppression via CCL3-driven M2 polarization.

Authors: Yue Li, Jin Cheng, Fei Liu, Junjie Yi, Zhefeng Li, Yanheng Yu, Mei Jiang, Xiaoting Zhao, Wentao Yue
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: High-grade serous ovarian carcinoma (HGSOC) is an aggressive malignancy marked by high recurrence rates, poor prognosis, and limited response to immune checkpoint inhibitors, primarily attributable to its immunologically "cold" tumor microenvironment (TME). To profile the immunological landscape of HGSOC, we conducted single-cell RNA sequencing (scRNA-seq) on 84,065 cells from tumor tissues of eight treatment-naïve patients and one normal ovarian tissue, identifying six major cell clusters and revealing substantial immune cell infiltration. Further analysis of CD8⁺ T cells identified two key subpopulations-precursor and terminally exhausted T cells-and delineated their developmental trajectories. The accumulation of exhausted CD8⁺ T cells (Tex) suggested an immunosuppressive TME. Integrated trajectory inference and high-dimensional weighted gene co-expression network analysis (hdWGCNA) identified CCL3 as a novel hub gene specifically expressed in Tex cells. Communication analysis suggested that Tex cells may interact with M2 macrophages via the CCL3-CCR1 ligand-receptor axis. Functional validation confirmed that: (1) secretomes from Tex cells-but not effector T cells-significantly promoted M2 polarization in both THP-1 and bone marrow-derived macrophages (CD206⁺ THP-1: 83.8% vs. 51.4%, p < 0.001; CD206⁺ BMDM: 72.4% vs. 41.5%, p < 0.001); and (2) recombinant CCL3 acted synergistically with IL-4/IL-10 to further enhance M2 polarization (59.2% vs. 37.7%, p = 0.008). Collectively, our findings unveil a previously unrecognized immunoregulatory axis whereby exhausted CD8⁺ T cells drive immunosuppression via CCL3-CCR1-mediated communication with M2 macrophages, presenting a promising therapeutic target to reverse the immune-cold TME in HGSOC.

Targeting STAT3-mediated lipid metabolism reprogramming overcomes chemoresistance in acute myeloid leukemia.

Targeting STAT3-mediated lipid metabolism to overcome chemoresistance in AML.

Authors: Keren Peng, Jianshan Mo, Zhenjiao Yang, Wen Ding, Jiayu Yan, Shumin Ouyang, Minyuan Lu, Kai Zhu, Hongru Yao, Huiqin Chen, Xiongjun Xu, Peibin Yue, Jinjian Lu, Yuanxiang Wang, Shanyi Zhang, Yandong Wang, Xiaolei Zhang
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Chemotherapy resistance and intolerance present significant challenges in the effective treatment of acute myeloid leukemia (AML). However, the role of metabolic reprogramming, particularly lipid metabolic rewiring, in promoting chemotherapy resistance in leukemia has not been fully elucidated. Here, we found that multiple lipid metabolism processes are aberrantly activated in Ara-C resistant AML cells, accompanied by upregulation of JAK-STAT3 signaling and key lipid metabolic regulators, notably SREBP1 and CPT2. Additionally, we discovered W1307, a potent and highly selective STAT3 inhibitor, which demonstrated significant anti-tumor activity both in vitro and in vivo. Genetic and pharmacological inhibition of STAT3 simultaneously suppresses lipid synthesis and catabolism, leading to lipids metabolic disorder accompanied with lipids accumulation, ROS increase, lipid peroxidation and mitochondrial membrane potential decrease. Mechanistically, STAT3 binds to DNA response elements in the promoters of the lipid metabolism associated gene SREBF1 and CPT2, and regulates their expression. Furthermore, inhibition of STAT3 enhances the anti-tumor effect of Ara-C and sensitizes resistant AML cell line to Ara-C through disrupting lipid homeostasis and triggering lipotoxicity. Our findings highlight the critical role of STAT3-driven lipid metabolism reprogramming in chemoresistance. Furthermore, W1307 emerges as a promising therapeutic candidate to overcome chemoresistance in leukemia treatment.

Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.

Interruption of fatty acid oxidation at HADHA node promotes tumoral ferroptosis.

Authors: Yuhan Zhou, Jing Li, Fangfang Liu, Yuan Gao, Songlin Yin, Liguo Yang, Xiaoxiao Li, Junhong Lin, Yan Li, Haotian Shang, Xiang Cheng, Tengfei Chao, Qian Chu, Fujia Lu, Weimin Wang
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.

Hypoxia-induced circSPECC1 drives temozolomide resistance in glioblastoma via IGF2BP2-mediated PGK1 mRNA stabilization.

Hypoxia-induced circSPECC1 drives temozolomide resistance in glioblastoma.

Authors: Yu Zeng, Liqian Zhao, Tianshi Que, Li Zhou, Xiaosheng Yang, Xin Xu, Kaihua Cao, Xizhao Wang, Xuhui Wang, Wenchuan Zhang, Ming Chen
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Glioblastoma (GBM) is a notoriously lethal brain tumor, primarily owing to its inevitable resistance to temozolomide (TMZ), a frontline chemotherapy. Hypoxia-driven metabolic adaptations have been implicated in therapeutic failure; however, the role of circular RNAs remains largely underexplored. By integrating multiomics profiling with functional assays in patient-derived GBM cells, orthotopic xenografts, and clinical specimens, this study aimed to elucidate the role of hypoxia-induced hsa_circ_0000745 (circSPECC1) in mediating TMZ resistance. Mechanistic investigation included RNA pulldown, RIP, glycolysis flux analysis, and DNA damage assessment. The circSPECC1 is overexpressed in GBM and correlates with poor prognosis. Hypoxia triggers HIF-1α-mediated transcriptional upregulation of circSPECC1, which scaffolds insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to stabilize phosphoglycerate kinase 1 (PGK1) mRNA. Importantly, circSPECC1/PGK1 axis activation enhances glycolytic flux, blunts TMZ-induced DNA damage, and confers chemoresistance. Targeting circSPECC1 disrupts PGK1-driven glycolysis, restores TMZ sensitivity, and synergizes with TMZ to extend survival in orthotopic GBM models. In conclusion, this study identifies a previously uncharacterized HIF-1α/circSPECC1/IGF2BP2/PGK1 axis that drives metabolic adaptation and TMZ resistance in GBM. Targeting this axis overcomes acquired chemoresistance, positioning circSPECC1 as both a prognostic biomarker and a therapeutic vulnerability in hypoxic GBM niches.

IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma.

IDH1-R132H mutation enhances oncolytic HSV-1 therapy in glioma.

Authors: Eleni Panagioti, Hunter J Kelley, Alexander L Ling, Leinal Sejour, Shikha Saini, William F Goins, Daniel Roberts, Sotiris Sotiriou, J Bryan Iorgulescu, Karen O Dixon, Michael B Yaffe, Ioannis S Vlachos, Maria G Castro, Sean E Lawler, Gordon J Freeman, Vijay K Kuchroo, E Antonio Chiocca, Charles H Cook
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Oncolytic virotherapy represents a promising yet under-explored approach for precision cancer treatment, particularly when tailored to tumor-specific molecular profiles. Patients with high-grade isocitrate dehydrogenase (IDH) mutant astrocytomas have limited treatment options and poor prognoses. Here, we investigate the therapeutic efficacy of rQNestin34.5 v.2 (CAN-3110), an engineered oncolytic herpes simplex virus 1 (oHSV-1), in IDH1-R132H-mutant diffuse gliomas. We demonstrate that the IDH1-R132H mutation enhances glioma susceptibility to viral infection through upregulation of Nectin-1, the main HSV-1 entry receptor. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, creating a permissive microenvironment that facilitates viral replication and tumor cell apoptosis. In immunocompetent murine glioma models, intratumoral administration of rQNestin34.5 v.2 induces robust antitumor immune activation, including increased immune infiltration and systemic IFN-γ release. However, elevated expression of poliovirus receptor (PVR) and the immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating leukocytes suggests a potential resistance mechanism to virotherapy. Combining rQNestin34.5 v.2 with TIGIT blockade enhances therapeutic efficacy compared to monotherapy, identifying IDH1-R132H as a potential predictive biomarker for oncolytic virotherapy response.

Metabolic activation of LDHA by ERRα represses inflammasome-dependent pyroptosis and promotes ovarian cancer chemoresistance.

ERRα/LDHA axis drives chemoresistance and suppresses pyroptosis in ovarian cancer.

Authors: Yuan Ren, Jingxuan Ye, Yonghong Zhang, Guanyu Ruan, Yashi Shi, Jincheng Ma, Hao Lin, Liang Wang, Liying Wang, Xite Lin, Maotong Zhang, Nan Wang, Xiaodan Mao, Pengming Sun
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Chemoresistance remains a major unmet challenge in the clinical management of ovarian cancer. As a metabolism-associated malignancy, the poor prognosis and frequent chemoresistance of ovarian cancer are closely linked to metabolic reprogramming. In this study, we identify estrogen-related receptor α (ERRα) as a key regulator of metabolic plasticity and chemoresistance in ovarian cancer. Bioinformatic analyses of pan-cancer datasets and chemoresistant ovarian cancer samples reveal that high expression of ERRα and the glycolytic rate-limiting enzyme lactate dehydrogenase A (LDHA) is associated with poor clinical outcomes. Elevated serum LDH levels in chemoresistant patients further underscore the importance of metabolic reprogramming in the development of chemoresistance. Mechanistically, ChIP-seq, dual-luciferase reporter assays, and enzymatic colorimetric assays demonstrate that ERRα directly binds to the LDHA promoter region (5'-AGAAGGTCG-3'), activating its transcription and enhancing glycolysis and the production of its end-product, lactate. Scanning electron microscopy, immunofluorescence, Western Blot, and other molecular functional assays show that the ERRα/LDHA axis drives lactate accumulation, downregulates inflammasome-related proteins (NLRP3, caspase-1, GSDMD and GSDMD-N), thereby suppressing pyroptosis and promoting resistance to cisplatin, carboplatin, and paclitaxel in ovarian cancer cells. Pharmacological inhibition of ERRα with XCT790 restores sensitivity to chemotherapeutic agents. In a mouse xenograft model, targeting ERRα enhances the therapeutic efficacy of chemotherapy. Collectively, these findings reveal that the ERRα-LDHA axis increases lactate production, bridging glycolytic metabolism and the suppression of pyroptosis, thereby facilitating chemoresistance in ovarian cancer. Targeting the ERRα/LDHA pathway and developing ERRα inhibitors may represent promising strategies to overcome chemoresistance in ovarian cancer.ERRα targets the promoter region of LDHA, promoting its transcription and the production of the glycolytic product lactate, inhibiting the NLRP3/caspase-1/GSDMD pathway, reducing cell pyroptosis, and helping ovarian cancer cells resist the cytotoxic effects of carboplatin and paclitaxel. Created in BioRender. Ren, Y. (2025) https://BioRender.com/qeh0dw8.

Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities.

iPSC-derived models of MPNST progression involving NF1, CDKN2A, and PRC2 loss.

Authors: Itziar Uriarte-Arrazola, Míriam Magallón-Lorenz, Juana Fernández-Rodríguez, Jiajing Zhang, Emily Lee, Sara Ortega-Bertran, Edgar Creus-Bachiller, Judit Farrés-Casas, Kelli M Wilson, Crystal McKnight, Katlin Recabo, Ignacio Blanco, Héctor Salvador, Cleofé Romagosa, Conxi Lázaro, Helena Mazuelas, Bernat Gel, Marc Ferrer, Meritxell Carrió, Eduard Serra
Source: PubMed
Publication date: 17 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. The progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) is not completely understood but commonly involves the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Here we use an iPSC-derived neural crest (NC) model to reproduce this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs form neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupts pluripotency and induces mesenchymal stem cell-like features. 3KO NCs undergo global chromatin reorganization that prevents gliogenesis by SOX10 silencing and activates neuro-mesenchymal transcriptional programs recapitulating PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres form MPNST-like tumors in vivo, mimicking an early-stage MPNST. Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model.

VEGFR2 inhibition potentiates STING-mediated antitumor immunity.

VEGFR2 inhibition potentiates STING-mediated antitumor immunity in cancer.

Authors: Fangping Han, Pengbo Sun, Yuanyuan Wei, Jing Han, Yi Wang, Rui Kuai, Conggang Zhang
Source: PubMed
Publication date: 18 June 2026
Primary category: Cancer biology
Priority: high
Abstract: STING bridges innate and adaptive immunity to exert potent antitumor effects, and its agonists play emerging roles in combination therapies with tyrosine kinase inhibitors (TKIs). However, the interaction between STING and receptor tyrosine kinases (RTKs) remains incompletely understood. Here, we identify VEGFR2 as a negative regulator of cGAMP-STING signaling. Upon cGAMP stimulation, both STING and VEGFR2 are activated. Activated VEGFR2 recruits and activates AKT1 to attenuate STING activation. Conversely, STING suppresses VEGFR2 phosphorylation, establishing a reciprocal inhibitory feedback loop. A cell-based screen reveals that the VEGFR2 inhibitor Ki8751 not only relieves VEGFR2-AKT1-mediated suppression but also activates MyD88-dependent NF-κB signaling to further amplify STING responses. Additionally, we show that Ki8751 synergizes with cGAMP to elicit robust, STING-dependent antitumor immunity in vivo. Our findings identify the VEGFR2-STING regulatory axis and provide a mechanistic rationale for co-targeting VEGFR2 and STING to improve cancer immunotherapy.

Argonaute 2 drives resistance to immune checkpoint inhibitors in immunorefractory non-small cell lung cancer.

Argonaute 2 drives resistance to immune checkpoint inhibitors in non-small cell lung cancer.

Authors: Dario Pasquale Anobile, Layla Barbar, Emile Maucotel, Alexis Cornec, Valeria Manriquez, Wilfrid Richer, Jordan Denizeau, Christine Sedlik, Charlie Bories, Elodie Couderc, Renaud Leclere, Judith Sobas, Emeline Papillon, Rafael Mena Osuna, Jimena Tosello-Boari, Marianne Burbage, Eliane Piaggio, Enzo Z Poirier
Source: PubMed
Publication date: 18 June 2026
Primary category: Cancer biology
Priority: high
Abstract: One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlates with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer.

Uses multiplexed mRNA to deliver cytokines and antigens to combat pancreatic cancer.

Authors: Chaitanya N Parikh, Kelly D DeMarco, Nikita Bhalerao, Hadiya K Giwa, Griffin I Kane, Ronnie W Dinnell, Boyang Ma, Haruka Mori, Meghan L Brassil, Katherine C Murphy, Zhen Zhao, Calvin Johnson, Shriram Ramani, Lin Zhou, Loretah Chibaya, Youwei Qiao, Kai Hu, Lihua Julie Zhu, Brian C Lewis, Wen Xue, Jason R Pitarresi, Prabhani U Atukorale, Marcus Ruscetti
Source: PubMed
Publication date: 19 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.

Neuron-targeting piezoelectric microneedles disrupt pro-tumorigenic neuron-immune crosstalk and restore anti-tumor immunity in melanoma.

Investigates neuron-immune crosstalk and cGAS-STING pathway in melanoma immunotherapy.

Authors: Anjun Song, Yanjie Zhang, Yanjun Ji, Heying Yuan, Jinsong Ren, Xiaogang Qu
Source: PubMed
Publication date: 19 June 2026
Primary category: Cancer biology
Priority: high
Abstract: Neuroimmunology has garnered significant attention due to its role in immune regulation, particularly in cancer, where infiltrating neurons can influence antigen presentation, T-cell activation, and cancer metastasis, ultimately leading to an inadequate immune response. Here, we integrate manganese-doped titanium-based metal-organic framework (MOF) piezoelectric materials (MT), coated with neuron-derived membranes from dorsal root ganglia, into microneedles (MN) to create a piezoelectric microneedle (MT MN) patch designed to disrupt neuron-immune crosstalk in melanoma. A single administration of MT via microneedle patch stably deposits the MT at the melanoma site in female mice to accelerate the nociceptor neurons targeting. Upon moderate ultrasound stimulation, the MT facilitates the internalization of TRPV1 and activates the cGAS-STING pathway, resulting in the reduction of Ca2+ influx in nociceptor neurons. This ultimately limits the production of calcitonin gene-related peptide (CGRP) and substance P (SP). Consequently, to rescue the tumor immune microenvironment damaged by infiltrated neurons, MT MN is utilized to inhibit the growth and infiltration of nociceptor neurons, highlighting a promising manner for interfering neuron-immune crosstalk in melanoma to enhance cancer immunotherapy.

CRISPR / gene editing

Guide RNA reprogramming facilitates minimized tracrRNA-dependent off-target and versatile CRISPR/Cas9 engineering.

Guide RNA reprogramming to minimize tracrRNA-dependent off-target effects in CRISPR/Cas9 engineering.

Authors: Wenxia Yu, Jun Chen, Junfan Guo, Fang Yu, Ge Wang, Jianxiang Lin, Xiangping Dai, Xinyi Tan, Peixiang Ma, Ligang Wu, Yu Zhang, Shisheng Huang, Pengfei Lan, Qian Bian, Xingxu Huang, Jiao Wei, Tianlin Cheng, Xiaoguo Zheng, Yunbo Qiao
Source: PubMed
Publication date: 17 June 2026
Primary category: CRISPR / gene editing
Priority: high
Abstract: While innovative, current CRISPR-Cas9 systems face safety concerns and practical hurdles, notably sequence-independent, noncanonical off-targeting. We demonstrate that the crRNA:tracrRNA duplex in guide RNAs (gRNA) is both splittable and reprogrammable. This property, however, enables endogenous RNAs with crRNA-like sequences to hijack any gRNAs, causing low-frequency yet pervasive tracrRNA-dependent off-target (TDO) effects. Using machine learning trained on high-throughput gRNA variant screens, we derive optimal gRNA-designing rules and engineer crRNA variants mismatched to the human/mouse transcriptomes, thereby minimizing TDO. By leveraging splittability and reprogrammability, we develop reprogrammable tracrRNAs for CRISPRa-based mRNA detection and redesign scaffolds to curb PAM-less Cas9-mediated "self-editing". We further create a separately expressed gRNA (segRNA) platform featuring split tracrRNAs and non-repetitive tandem crRNAs, enabling multiplexed editing of up to six genes and functional enhancer annotation in stem cells. Our findings uncover a previously overlooked off-target mechanism and offer versatile strategies to enhance the safety and utility of CRISPR systems.

Deep learning-guided engineering of SpuFz1 and rational miniaturization of ωRNA enables efficient genome editing.

Uses deep learning to engineer the Fanzor nuclease (enFanzor) and optimize omegaRNA for genome editing.

Authors: Shuanghong Chen, Shenlin Hsiao, Tian Xie, Danni Chen, Naixin Chen, Jing Jiang, Jinsong Li, Yuxuan Wu, Jiaoyang Liao
Source: PubMed
Publication date: 18 June 2026
Primary category: CRISPR / gene editing
Priority: high
Abstract: Advancing the performance of programmable genome editing nucleases remains a key challenge in expanding their research and therapeutic applications. Here, we introduce a scalable deep learning-guided protein engineering framework for improving nuclease activity without requiring experimental training data. As a demonstration, we apply this strategy to SpuFz1, a compact Fanzor nuclease of eukaryotic origin, identifying and validating beneficial mutations that produces a multi-mutant variant with an 11.6-fold increase in editing efficiency. In parallel, we use comparative sequence analysis to design and experimentally validate a 75-nt ultrashort ωRNA scaffold, reducing guide RNA length by 79% while maintaining activity. Integration of these optimized components yields enFanzor, a compact genome editing system that achieves editing efficiencies up to 81.9% in mammalian cells, with strong editing performance in both human hematopoietic stem and progenitor cells (HSPCs) and mouse embryos. The outperforming variant developed through this strategy also supports robust CBE and ABE activity. Notably, the shortened ωRNA not only improves nuclease editing specificity but also leads to a substantial increase in base editing efficiency. Together, this work demonstrates the power of combining AI-guided protein optimization with rational RNA design, and establishes a generalizable strategy for engineering next-generation genome editing tools.

Other biology

Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.

Reverse engineering of BNIP3 to identify a mitochondrial protective peptide for therapeutic use.

Authors: Ulrike B Hendgen-Cotta, Anna Roth, Christine Beuck, Daniel Messiha, Stephan Settelmeier, Shah Bahrullah Shah, Sebastian Korste, Kenny Bravo-Rodriguez, Mike Blueggel, Feyza Cansiz, Luiza Martins Nascentes Melo, Jonas Roesler, Sven W Meckelmann, Oliver J Schmitz, Farnusch Kaschani, Markus Kaiser, Sonja Esfeld, Omar El Bounkari, Jürgen Bernhagen, Sophie Brameyer, Kirsten Jung, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Matthias Totzeck, Thomas Minor, Michael Ehrmann, Alpaslan Tasdogan, Peter Bayer, Tienush Rassaf
Source: PubMed
Publication date: 17 June 2026
Primary category: Other biology
Priority: high
Abstract: Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence-function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.

APOE4 Drives Uniquely Dysfunctional Human Microglial States in Alzheimer's Disease

Shows how APOE4 drives dysfunctional microglial states in Alzheimer's disease.

Authors: Ee, R., Amouzgar, M., Afaghani, J., Vijayaragavan, K., Cannon, B. J., Mrdjen, D., Tebaykin, D., Spence, A., Sant, C., Aley, D., Guo, Z., Sedov, K., Zafar, F., Montine, K. S., Perna, A., Serrano, G. E., Beach, T. G., Angelo, M., Schüle, B., Corces, M. R., Montine, T. J., Bendall, S. C.
Source: bioRxiv
Publication date: 19 June 2026
Primary category: Other biology
Priority: high
Abstract: Variation in APOE, notably the {epsilon}4 allele, profoundly shapes risk and severity of late-onset Alzheimer's disease (AD), yet how it remodels human microglial states remains unresolved. We combine spatially resolved proteomic profiling with single-nuclear multiomic analyses to define microglial organization across APOE3/3 and APOE4/4 genotypes in AD. Quantifying condition-associated variation across the cellular manifold reveals a continuous landscape of microglial states. APOE4/4 shifts cells toward terminal states marked by loss of homeostatic identity, metabolic disruption, and incomplete acquisition of disease-associated programs. We identify an APOE4/4-enriched population in AD that exhibits inflammatory signaling without effective metabolic or phagocytic engagement, localizing to niches of gliosis and senescence, and coupled to chronic stress adaptation programs. Together with evidence that APOE4/4 potentiates the activation threshold of nascent microglia, these findings establish a unified framework for human microglial state change, linking genetic risk to spatial and molecular organization of immune responses in the AD brain.