Cell Reports

CGRP signaling links tumor-associated pain to immune evasion in oral squamous cell carcinoma McIlvried et al. report an inverse relationship between patient-reported pain and tumor-infiltrating lymphocytes in patients with oral cancer. Using gain- and loss-of-function approaches in syngeneic mouse models, they establish that tumor-evoked nociceptor activation drives CGRP-mediated immunosuppression. They then show that CGRP receptor antagonism reduces both tumor-associated pain and immune evasion.

CGRP signaling links tumor-associated pain to immune evasion in oral squamous cell carcinoma

Insulin-like growth factor signaling regulates zebrafish lymphatic-vessel development Chen et al. have discovered that IGF signaling acts locally to promote the migration of a lymphatic vessel along the craniofacial cartilage. They also demonstrate that IGF1R signaling promotes both zebrafish and human lymphatic cell migration, indicating that IGF signaling has a conserved role in lymphatic-vessel development.

Insulin-like growth factor signaling regulates zebrafish lymphatic-vessel development

In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development Human γδ T cells differ greatly from mouse γδ T cells. La et al. report that it is possible to generate bona fide human γδ T cells in a humanized immune system mouse model. Additionally, they show that TdT controls the development of type 3 Vδ2 T cells.

In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development

Liquid-liquid phase separation of EphB4 drives pulmonary hypertension via YAP activation Liu et al. reveal that vascular stiffening drives pulmonary hypertension by inducing EphB4 to undergo phase separation in smooth muscle cells. These condensates trap YAP inhibitors, unleashing pathogenic proliferation. A targeted peptide disrupts condensation and attenuates pulmonary hypertension in vivo, revealing a new mechanotherapeutic strategy.

Liquid-liquid phase separation of EphB4 drives pulmonary hypertension via YAP activation

Genomic foundations of salt tolerance in desert cyanobacteria Ye et al. uncover the genetic changes enabling a desert cyanobacterium to thrive in hypersaline soils through genomic, evolutionary, and functional analyses, and reveal how structural rearrangements, key pathway collaboration, and important amino acid accumulation collectively underpin extreme environmental adaptation.

Genomic foundations of salt tolerance in desert cyanobacteria

Single-cell multi-omic analyses highlight the essential role of NKX2.2-CLEC16A/endosomal pathway for human pancreatic differentiation and function Chen et al. provide a comprehensive roadmap of the gene regulatory networks governing human pancreatic differentiation and identify the essential roles of the NKX2.2-CLEC16A/endosomal pathway axis for islet organogenesis. This study also highlights the expandable pancreatic progenitor (ePP)-islet system as a powerful platform for investigating cell fate decisions and disease modeling.

Single-cell multi-omic analyses highlight the essential role of NKX2.2-CLEC16A/endosomal pathway for human pancreatic differentiation and function

Nuclear import of malaria RNA rewires splicing in host immune cells Abou Karam et al. identify a cell communication mechanism used by the malaria parasite Plasmodium falciparum. The parasite delivers its mRNAs into monocytes and imports them into their protected nuclei, where they perturb the splicing. This extracellular RNA-based strategy disrupts host transcript processing and immune signaling, revealing another layer of host interference.

Nuclear import of malaria RNA rewires splicing in host immune cells

Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability Abou Alaiwi et al. generate a comprehensive epigenomic atlas of clear cell renal cell carcinoma, revealing that enhancer reprogramming and reactivation of fetal kidney developmental programs drive tumorigenesis. The cistrome-wide association study in ccRCC identifies novel HIF2α-mediated risk loci, with functional validation of a SCARB1 regulatory enhancer.

Generation of a comprehensive epigenomic atlas in clear cell renal cell carcinoma informs kidney cancer progression and heritability

A p63-dependent molecular switch directs epithelial fate to form a specialized seal at the tooth-gingiva interface Liang et al. show that a p63-RUNX1-ODAM axis directs gingival progenitors toward a specialized sealing fate rather than keratinization. This molecular switch explains the clinical success of niche-preserving surgeries and provides a biological rationale for regenerating the tooth-gum interface to treat periodontitis.

A p63-dependent molecular switch directs epithelial fate to form a specialized seal at the tooth-gingiva interface

Toxoplasma gondii infection misdirects placental trophoblast lineage specification Cabo et al. have identified a novel consequence of congenital Toxoplasma gondii infection. They have characterized how the parasite manipulates placental trophoblast development to prevent the physical formation of a cell type that is infection resistant. Antagonism of this cell type affects disease outcome and parasite transmission dynamics in the human placenta.

Toxoplasma gondii infection misdirects placental trophoblast lineage specification

Pathogen effector disarms circadian-immune crosstalk by targeting TCP14, a dual regulator of clock and defense Wang et al. identify the transcription factor TCP14 as a critical nexus linking the circadian clock and plant defense. The study reveals how the pathogen effector HaRxL21 hijacks this connection by recruiting TPL/TPR1 repressors to disarm TCP14, thereby providing a mechanistic understanding of how pathogens overcome circadian-gated immunity.

Pathogen effector disarms circadian-immune crosstalk by targeting TCP14, a dual regulator of clock and defense

Hepatocyte PLAGL2 deficiency alleviates MASH through MYD88-licensed inactivation of inflammasome Duan et al. systematically delineate the spatiotemporal dynamics and key regulators of pyroptosis during MASLD progression. Hepatocyte-specific Plagl2 deletion alleviates MASH by suppressing MYD88-mediated inflammasome activation and restoring metabolic homeostasis. Pyroptosis-driven IL-1β release promotes macrophage differentiation into a phagocytosis-enhanced, JAK/STAT-activated, NASH-associated phenotype.

Hepatocyte PLAGL2 deficiency alleviates MASH through MYD88-licensed inactivation of inflammasome

Quantitative genetics of natural S. cerevisiae strains upon mating reveal heritable determinants of fitness and differential mating affinities Strauss et al. utilize a high-throughput recombination platform to uncover the rules of yeast mating. They report that yeast display adaptive mate affinity and show that environmental context dictates which parental characteristics best predict offspring fitness, revealing a dynamic interplay between sexual selection and environmental adaptation.

Quantitative genetics of natural S. cerevisiae strains upon mating reveal heritable determinants of fitness and differential mating affinities

Proteasome activity maintains cell-type-specific gene expression Lu et al. demonstrate that the proteins with the greatest changes in abundance following proteasome impairment are altered transcriptionally and that these proteins are canonically expressed with cell type specificity. Impaired degradation of the deubiquitinase OTUD5 contributes to this dysregulation.

Proteasome activity maintains cell-type-specific gene expression

Feedback control of random networks as a model of flexible motor cortical dynamics across tasks Kalidindi and Crevecoeur develop a computational framework linking feedback-controlled networks to limb dynamics. They demonstrate that optimal control of fixed network reproduces key motor cortical dynamics and predicts neural activity across tasks. Analytical results show low-dimensional patterns emerge from task and biomechanical complexity, thereby bridging neural dynamics with control theory.

Feedback control of random networks as a model of flexible motor cortical dynamics across tasks

Bacterial defense systems and host ecology drive the evolution of intra-species lineages Staphylococcus aureus lineages vary widely in the frequency of gene exchange and the diversity of genome content. Gorzynski and Harling-Lee et al. show that both host ecology and the horizontal acquisition of DNA defense genes are major forces in shaping the lineage structure and genome dynamics of S. aureus populations.

Bacterial defense systems and host ecology drive the evolution of intra-species lineages

Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination Lee et al. reveal that short-term acidosis suppresses cancer cell aggressiveness across cell types. Hypoxia overrides acidosis-mediated inhibition of motility by restoring NHE1/ILK function and maintaining bioenergetic balance through compensatory glycolysis. Adaptation to chronic acidosis is cell-specific and depends on a cell’s ability to restrain ROS via fatty acid oxidation.

Hypoxia restores the acidosis-induced inhibition of cancer cell dissemination

High-throughput engineered tumor organoids reveal ROCK signaling as an immunotherapeutic target in triple-negative breast cancer Ma et al. developed a TIL-competent triple-negative breast cancer (TNBC) organoid model recapitulating the immune microenvironment. They identified pentanoic acid as a ROCK activator that preserves tumor-infiltrating lymphocytes and enhances the anti-PD-1 immunotherapy efficacy, providing potential precision medicine strategies for aggressive basal-like immune-suppressed (BLIS) subtypes.

High-throughput engineered tumor organoids reveal ROCK signaling as an immunotherapeutic target in triple-negative breast cancer

Circadian rhythm heterogeneity modulates drug response variations in neuroblastoma models Ector et al. uncover circadian heterogeneity across neuroblastoma cell models and link rhythmic strength to drug sensitivity. Their findings suggest that circadian competence may influence treatment outcomes, pointing to chronotherapy as a potential avenue for improving pediatric cancer care.

Circadian rhythm heterogeneity modulates drug response variations in neuroblastoma models

A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs Wang et al. systematically analyzed mitochondria-localized lncRNAs to reveal that RBP-motif recognition drives RNA mitochondrial translocation, leading to the engineering of an RNA mitochondrial targeting sequence (RMTS). Fusing RMTS with sgRNA promotes sgRNA mitochondrial entry, establishing a CRISPR-based mitochondrial DNA editing system that ameliorates heteroplasmic mtDNA mutation diseases.

A CRISPR-based mitochondrial gene therapy tool derived by engineering guide RNAs

Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity Fungal infections can induce ER stress, but whether ER stress affects antifungal immune signaling remains unclear. Wu et al. reveal that upon fungal stimulation, the PERK branch of the unfolded protein response pathway is activated by triglyceride synthesis and then mediates autophagic degradation of SHP-1 to amplify SYK-associated antifungal immunity.

Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity

RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio Ström et al. identify the rs115660502 variant in RAB3GAP2 associated with increased skeletal muscle capillary-to-fiber ratio and enriched in endurance athletes. This variant reduces RAB3GAP2 expression, enhancing endothelial proliferation, tube formation, and TNC secretion, thereby promoting exercise-like angiogenesis and microvascular remodeling in skeletal muscle.

RAB3GAP2 is a regulator of skeletal muscle endothelial cell proliferation and associated with capillary-to-fiber ratio

A bicistronic viral genome uses a compact type IV IRES near its 3′ end to express a transmembrane protein Sherlock et al. examine an IRES RNA that initiates translation of a small downstream coding region within a viral genome. The structure, function, and mechanism of this IRES are interrogated experimentally. Differential translation efficiencies between two IRESs within one viral genome exemplify RNA-structure-based tuning of gene expression.

A bicistronic viral genome uses a compact type IV IRES near its 3′ end to express a transmembrane protein

Nuclear PD-L1 regulates YAP-driven transcription via the PGE2-EP4-YAP-importin α3 axis in solid tumors Satapathy et al. demonstrate that prostaglandin E2 promotes YAP-dependent nuclear translocation of PD-L1 via importin-α3. In the nucleus, PD-L1 cooperates with YAP-TEAD to enhance transcriptional activity, revealing a noncanonical role for PD-L1 in regulating oncogenic gene expression beyond immune evasion.

Nuclear PD-L1 regulates YAP-driven transcription via the PGE2-EP4-YAP-importin α3 axis in solid tumors

For a chance to present your research as a poster or short talk @CellSymposia #CSMito2026 in Glasgow, Scotland, June 21–23, 2026, submit an abstract of your work before March 9
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Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death Mg2+ is crucial for various cellular functions, but the effect of intracellular Mg2+ decrease remains obscure. Kawamura et al. show that the decrease triggers massive cell death by activating the NF-κB signal. Furthermore, cell death is distinct from the known types of regulated cell death, which are characterized by actin-driven protrusions.

Cellular Mg2+ decrease causes a distinctive NF-κB-dependent form of cell death

Tfam-mediated metabolic perturbation in RORγt+ lymphocytes impacts intestinal tissue homeostasis and promotes GATA3+RORγt+ innate lymphoid cells Sun et al. report an indispensable role for Th2 cells in small intestine lengthening driven by tuft cell type 2 immunity and a population of GATA3+RORγt+ ILCs promoted by Tfam deficiency, high-fat diet, and DSS-induced gut inflammation in mice. GATA3+RORγt+ ILCs exhibit transcriptional and metabolic profiles distinct from that of conventional ILC3s.

Tfam-mediated metabolic perturbation in RORγt+ lymphocytes impacts intestinal tissue homeostasis and promotes GATA3+RORγt+ innate lymphoid cells

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Excited to hear @nataliekrahmer.bsky.social discuss "Elucidating the cell architecture of metabolic liver disease" at Cell Press Symposia #CSMito2026 (June 21–23, 2026, Glasgow, Scotland)
Submit an abstract before March 9 to join her: http://dlvr.it/TRBjrq

MARK2 serves as a key regulator of host antiviral immunity through GEF-H1 phosphorylation Wang et al. identify MARK2 as a key regulator of innate antiviral immunity. The phosphorylation of GEF-H1 at Ser645 by MARK2 enhances TBK1 activation and induces IFN-β andIFN-stimulated genes. This establishes the MARK2-GEF-H1-TBK1 axis as a fundamental component of host antiviral defense.

MARK2 serves as a key regulator of host antiviral immunity through GEF-H1 phosphorylation

Revealing an unconventional JAK1/2-STAT3 branch in macrophage IFN-γ signaling Botman et al. reveal that IFN-γ can rapidly activate STAT3 in macrophages, forming STAT1-STAT3 heterodimers that fine-tune gene expression. This discovery uncovers a new layer of complexity in cytokine signaling and macrophage activation, broadening our understanding of immune regulation.

Revealing an unconventional JAK1/2-STAT3 branch in macrophage IFN-γ signaling