Int J Mol Sci. 2025 Mar 25;26(7):2958. doi: 10.3390/ijms26072958.

ABSTRACT

The phosphate starvation response (PHR) transcription factor family play central regulatory roles in nutrient signaling, but its relationship with other abiotic stress remains elusive. In the woody plant Eucalyptus grandis, we characterized 12 EgPHRs, which were phylogenetically divided into three groups, with group I exhibiting conserved structural features (e.g., unique motif composition and exon number). Notably, a protein-protein interaction network analysis revealed that EgPHR had a species-specific protein-protein interaction network: EgPHR6 interacted with SPX proteins of multiple species, while Eucalyptus and poplar PHR uniquely bound to TRARAC-kinesin ATPase, suggesting functional differences between woody and herbaceous plants. A promoter sequence analysis revealed a regulatory network of 59 transcription factors (TFs, e.g., BPC, MYBs, ERFs and WUS), mainly associated with tissue differentiation, abiotic stress, and hormonal responses that regulated EgPHRs' expression. Transcriptomics and RT-qPCR gene expression analyses showed that all EgPHRs dynamically responded to phosphate (Pi) starvation, with the expression of EgPHR2 and EgPHR6 exhibiting sustained induction, and were also regulated by salt, cold, jasmonic acid, and boron deficiency. Strikingly, nitrogen starvation suppressed most EgPHRs, highlighting crosstalk between nutrient signaling pathways. These findings revealed the multifaceted regulatory role of EgPHRs in adaptation to abiotic stresses and provided insights into their unique evolutionary and functional characteristics in woody plants.

PMID:40243569 | DOI:10.3390/ijms26072958

Int J Mol Sci. 2025 Mar 22;26(7):2899. doi: 10.3390/ijms26072899.

ABSTRACT

The inevitable exposure of humans to micro/nanoplastics has become a pressing global environmental issue, with growing concerns regarding their impact on health. While the direct effects of micro/nanoplastics on human health remain largely unknown, increasing attention is being given to their potential role as carriers of environmental pollutants and organic substances. This study investigates the direct toxicity of 500 nm polystyrene nanoplastics (NPs) on human hepatocytes (HepG2) in vitro, both alone and in combination with cadmium (Cd), a hazardous heavy metal and a prevalent environmental pollutant. One-hour exposure to 100 µg/mL of NPs causes a significant increase in ROS production (+25% compared to control) but cell viability remains unaffected even at concentrations much higher than environmental levels. Interestingly, NPs significantly reduce Cd cytotoxicity at LC50 concentrations (cell viability compared to control: 55.4% for 50 µM Cd, 66.9% for 50 µM Cd + 10 µg/mL NPs, 68.4% for 50 µM Cd + 100 µg/mL NPs). Additionally, NPs do not alter the cellular lipid content after short-term exposure (24 h). However, when Cd and fatty acids are added to the medium, NPs appear to sequester fatty acids, reducing their availability and impairing their uptake by cells in a dose-dependent manner. We confirmed by Dynamic Light Scattering and Scanning Electron Microscopy the interaction between NPs, Cd and free fatty acids. Although polystyrene NPs exhibited minimal cytotoxicity in our experimental model, collectively our findings suggest that predicting the effects of cell exposure to NPs is extremely challenging, due to the potential interaction between NPs, environmental pollutants and specific components of the biological matrix.

PMID:40243532 | DOI:10.3390/ijms26072899

Microbiol Immunol. 2025 Apr 17. doi: 10.1111/1348-0421.13219. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) is the primary form of liver cancer that poses a significant global health concern due to its increasing incidence rates and diverse etiology. Chronic infection induced by hepatitis B virus (HBV) is a prominent etiological factor influencing the development of HCC. Although recent advances in multi-omics approaches have facilitated extensive exploration of HCC molecular characteristics, translating the characteristics of subtypes into clinical applications has been challenging due to parameters like limited sample size and complex classifiers for early detection. In the present study, we performed transcriptomics profiling of HBV-infected HCC patient tissue data to gather comprehensive insights into the intricate molecular mechanisms underlying HBV-associated HCC, specifically, viral protein interactions that influence the expression of oncogenes. The 1059 differentially expressed genes (DEGs) identified across two GEO data sets revealed upregulation of cell cycle and mitosis-related genes, alongside downregulation of genes involved in fatty acid degradation and cytochrome P450 activity. CDK1 and CDC20 which are part of the top cluster and hub gene from interactome analysis were identified as potential markers for HBV-positive HCC through gene expression pattern and overall survival analysis. Additionally, 19 DEGs showing significance in HCC development were identified as interacting partners with HBV proteins. Among them, the interaction of HBsAg with ALB and SHBG and their downregulation correlates to the lower testosterone levels identified in HBV and HCC patients. Together, the study enhances the understanding of the heterogeneity and molecular pathogenesis of HBV-positive HCC.

PMID:40243270 | DOI:10.1111/1348-0421.13219

Ecol Evol. 2025 Apr 15;15(4):e71200. doi: 10.1002/ece3.71200. eCollection 2025 Apr.

ABSTRACT

Strategies of coexistence with large carnivores should integrate scientific evidence, population monitoring providing an opportunity for advancing outdated management paradigms. We estimated wolf population density and social dynamics across a 1400 km2 area in a data-poor region of the Romanian Carpathians. Across three consecutive years (2017-2018 until 2019-2020), we collected and genotyped 505 noninvasive DNA wolf samples (scat, hair and urine) to identify individuals, reconstruct pedigrees, and check for the presence of hybridization with domestic dogs. We identified 27 males, 20 females, and one F1 wolf-dog hybrid male. We delineated six wolf packs, with pack size varying between two and seven individuals, and documented yearly changes in pack composition. Using a spatial capture-recapture approach, we estimated population density at 2.35 wolves/100 km2 (95% BCI = 1.68-3.03) and population abundance at 70 individuals (95% BCI = 49-89). Noninvasive DNA data collection coupled with spatial capture-recapture has the potential to inform on wolf population size and dynamics at broader spatial scales, across different sampling areas representative of the diverse Carpathian landscapes, and across different levels of human impact, supporting wildlife decision making in one of Europe's main strongholds for large carnivores.

PMID:40242802 | PMC:PMC12000540 | DOI:10.1002/ece3.71200

Front Genet. 2025 Apr 2;16:1528935. doi: 10.3389/fgene.2025.1528935. eCollection 2025.

ABSTRACT

High-altitude polycythemia (HAPC) represents a pathological escalation of the physiological erythrocytosis induced by chronic hypoxia exposure. While moderate erythroid expansion enhances oxygen delivery, HAPC manifests as hematologic disorder characterized by hemoglobin thresholds (≥21 g/dL males; ≥19 g/dL females) and multi-organ complications including microcirculatory thrombosis, right ventricular hypertrophy, and uric acid dysmetabolism. This review critically evaluates the continuum between adaptive and maladaptive polycythemia through multiscale analysis of erythrocyte biology. We integrate genomic predisposition patterns, bone marrow erythroid kinetic studies, and peripheral erythrocyte pathophenotypes revealed by multi-omics profiling (iron-redox proteome, hypoxia-metabolome crosstalk). Current diagnostic limitations are highlighted, particularly the oversimplification of hemoglobin cutoffs that neglect transitional dynamics in erythrocyte turnover. By reconstructing the erythroid life cycle-from hypoxia-sensitive progenitor commitment to senescent cell clearance-we propose a phase transition model where cumulative epigenetic-metabolic derangements overcome homeostatic buffers, triggering pathological erythroid amplification. These insights reframe HAPC as a systems biology failure of erythroid adaptation, informing predictive biomarkers and targeted interventions to preserve hematological homeostasis in hypoxic environments.

PMID:40242475 | PMC:PMC12000012 | DOI:10.3389/fgene.2025.1528935

JHEP Rep. 2025 Jan 30;7(5):101338. doi: 10.1016/j.jhepr.2025.101338. eCollection 2025 May.

ABSTRACT

BACKGROUND & AIMS: Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers.

METHODS: Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts. They were analyzed using untargeted proteomics with mass spectroscopy and a serum cytokine profiling and compared with 30 healthy controls. The primary clinical outcome was 21-day transplant-free survival. Single-cell RNAseq data mapped biomarkers to cells of origin; functional enrichment analysis provided mechanistic insights. Novel prognostic scores were compared with the model for end-stage liver disease and ALFSG prognostic index scores.

RESULTS: In the discovery cohort, 117 proteins differed between patients with ALF and healthy controls. There were 167 proteins associated with APAP-related ALF, with the majority being hepatocyte-derived. Three hepatocellular proteins (ALDOB, CAT, and PIGR) robustly and reproducibly discriminated APAP from non-APAP cases (AUROCs ∼0.9). In the discovery cohort, 37 proteins were related to 21-day outcome. The key processes associated with survival were acute-phase response and hepatocyte nuclear factor 1α signaling. SERPINA1 and LRG1 were the best individual discriminators of 21-day transplant-free survival in both cohorts. Two models of blood-based proteomic biomarkers outperformed the model for end-stage liver disease and ALFSG prognostic index and were reproduced in the validation cohort (AUROCs 0.83-0.86) for 21-day transplant-free survival.

CONCLUSIONS: Proteomics and cytokine profiling identified new, reproducible biomarkers associated with APAP etiology and 21-day outcome. These biomarkers may improve prognostication and understanding of the etiopathogenesis of ALF but need to be independently validated.

IMPACT AND IMPLICATIONS: Acute liver failure (ALF) is a sudden, and severe condition associated with high fatality. More sensitive and specific prognostic scores are urgently needed to facilitate decision-making regarding liver transplantation in patients with ALF. Our proteomic analysis uncovered marked differences between acetaminophen and non-acetaminophen-related ALF. The identification of routinely measurable biomarkers that are associated with 21-day transplant-free survival and the derivation of novel prognostic scores may facilitate clinical management as well as decisions for/against liver transplantation. Further studies are needed to quantify less abundant proteins. Although we used two cohorts, our findings still need to be independently and prospectively validated.

PMID:40242314 | PMC:PMC11998117 | DOI:10.1016/j.jhepr.2025.101338

Front Cell Neurosci. 2025 Apr 2;19:1548252. doi: 10.3389/fncel.2025.1548252. eCollection 2025.

ABSTRACT

The dorsal horn of the spinal cord represents the first site in the central nervous system (CNS) where nociceptive signals are integrated. As a result, there has been a rapid growth in the number of studies investigating the ionic mechanisms regulating the excitability of dorsal horn neurons under normal and pathological conditions. We believe that it is time to look back and to critically examine what picture emerges from this wealth of studies. What are the actual types of neurons described in the literature based on electrophysiological criteria? Are these electrophysiologically-defined subpopulations strongly linked to specific morphological, functional, or molecular traits? Are these electrophysiological properties stable, or can they change during development or in response to peripheral injury? Here we provide an in-depth overview of both early and recent publications that explore the factors influencing dorsal horn neuronal excitability (including intrinsic membrane properties and synaptic transmission), how these factors vary across distinct subtypes of dorsal horn neurons, and how such factors are altered by peripheral nerve or tissue damage. The meta-research presented below leads to the conclusion that the dorsal horn is comprised of highly heterogeneous subpopulations in which the observed electrophysiological properties of a given neuron often fail to easily predict other properties such as biochemical phenotype or morphology. This highlights the need for future studies which can more fully interrogate the properties of dorsal horn neurons in a multi-modal manner.

PMID:40241846 | PMC:PMC12001243 | DOI:10.3389/fncel.2025.1548252

iScience. 2025 Feb 27;28(4):112111. doi: 10.1016/j.isci.2025.112111. eCollection 2025 Apr 18.

ABSTRACT

Drosophila fat body-derived SPARC acts as a chaperone for collagen IV (Col(IV)), enabling their diffusion and incorporation into distal tissue basement membranes (BMs). Disruption of SPARC or Col(IV) production by the fat body is lethal, despite expression by other tissues such as imaginal discs. Wing disc-derived SPARC does not associate with Col(IV) in BMs and is not essential for survival. We show that differential association of fat body- and wing disc-derived SPARC with Col(IV) is not due to differences in SPARC glycosylation nor to the absence of SPARC and Col(IV) co-expression. Further, we demonstrate that SPARC domain II/III produced by the fat body is sufficient for Col(IV) diffusion to both proximal and distal BMs, and rescues lethality associated with loss of SPARC. However, SPARC domain II/III does not diffuse beyond the hemolymph. Thus, the essential Col(IV) chaperone-like activity specific to fat body-derived SPARC is not required beyond the hemolymph.

PMID:40241767 | PMC:PMC12002606 | DOI:10.1016/j.isci.2025.112111

iScience. 2025 Mar 22;28(4):112266. doi: 10.1016/j.isci.2025.112266. eCollection 2025 Apr 18.

ABSTRACT

Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8+ T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.

PMID:40241752 | PMC:PMC12003012 | DOI:10.1016/j.isci.2025.112266

Front Physiol. 2025 Apr 2;16:1520826. doi: 10.3389/fphys.2025.1520826. eCollection 2025.

ABSTRACT

Over the past decades, MDV has dramatically evolved towards more virulent strains and remains a persistent threat to the world's poultry industry. We performed genome-wide gene expression analysis in the spleen, thymus, and bursa tissues from MD-resistant line and susceptible line to explore the mechanism of MD resistance and susceptibility. We identified genes and pathways associated with the transcriptional response to MDV infection using the robust RNA sequencing approach. The transcriptome analysis revealed a tissue-specific expression pattern among immune organs when confronting MDV. At pathway and network levels, MDV infections influenced cytokine-cytokine receptor interaction and cellular development in resistant and susceptible chicken lines. Meanwhile, we also observed different genetic responses between the two chicken lines: some pathways like herpes simplex infection and influenza A were found in MD resistant line spleen tissues, whereas metabolic-related pathways and DNA replication could only be observed in MD susceptible line chickens. In summary, our research renders new perceptions of the MD progression mechanism and beckons further gene function studies into MD resistance.

PMID:40241721 | PMC:PMC12000659 | DOI:10.3389/fphys.2025.1520826

New Phytol. 2025 Apr 16. doi: 10.1111/nph.70150. Online ahead of print.

NO ABSTRACT

PMID:40241401 | DOI:10.1111/nph.70150

J Agric Food Chem. 2025 Apr 16. doi: 10.1021/acs.jafc.5c00903. Online ahead of print.

ABSTRACT

Retrograde signaling regulates plant senescence, but the role of vacuoles in this process remains unclear. Here, we demonstrate that rice vacuolar H+-ATPase subunit A (OsVHA-A) localizes to both the cytoplasm and nucleus. Sucrose treatment increased OsVHA-A expression and nuclear accumulation, while darkness reduced it. Methyl jasmonate (MeJA) initially promoted OsVHA-A nuclear translocation but decreased it upon prolonged exposure. Downregulation of OsVHA-A expression accelerated MeJA-induced rice leaf senescence but delayed darkness-induced senescence. MeJA treatment also significantly upregulated the expression of OsMYC2 and OsMAPK6 in OsVHA-A-RNAi plants compared to wild-type plants. Moreover, OsVHA-A downregulation notably increased the level of expression of genes associated with sugar signaling and transport under dark conditions. Immunoprecipitation-mass spectrometry and molecular docking analyses identified interactions between OsVHA-A and OsTPR1, OsMed14, sucrose transporters, and enzymes involved in sucrose metabolism. The binding of OsVHA-A with OsTPR1 and OsSUS1 was confirmed by BiFC. These findings highlight the multifunctional role of OsVHA-A in coordinating organelles and nuclear signaling, providing new insights and potential strategies for manipulating senescence to improve rice yield and quality.

PMID:40241244 | DOI:10.1021/acs.jafc.5c00903

Sci Data. 2025 Apr 16;12(1):645. doi: 10.1038/s41597-025-04968-z.

ABSTRACT

Bougainvillea glabra is an ornamental tree or shrub with nearly 200 years of application in gardening and landscapes globally. Recently, the growing research interest in the applications of B. glabra extracts, such as medicinal applications, and synthetic materials for nutraceuticals, has led to the development of new techniques to be utilized for studying B. glabra. Moreover, the formations of polymorphic coloration and the mechanism of metamorphic bracts in B. glabra cultivars are worthy of study. However, the multi-omics information for B. glabra cultivars is lacking which hinders the progress of gene-level research and genetic applications. We sequenced the bracts transcriptomes of 22 B. glabra accessions and generated more than 80 Gb clean data. After de novo assembly and optimization, 174,758 unigenes (E90N50 = 2,473 bp) and annotation data were obtained. In addition, a total of 100,115 CDSs were detected. On average, each variety has 69,990 unigenes containing SNPs, among which 35,682 were annotated per variety. These transcriptome data are valuable for gene mining and expression experiments or other scientific areas.

PMID:40240768 | DOI:10.1038/s41597-025-04968-z

Nat Plants. 2025 Apr 16. doi: 10.1038/s41477-025-01979-x. Online ahead of print.

ABSTRACT

Short-read RNA-seq studies of grafted plants have led to the proposal that thousands of messenger RNAs (mRNAs) move over long distances between plant tissues1-7, potentially acting as signals8-12. Transport of mRNAs between cells and tissues has been shown to play a role in several physiological and developmental processes in plants, such as tuberization13, leaf development14 and meristem maintenance15; yet for most mobile mRNAs, the biological relevance of transport remains to be determined16-19. Here we perform a meta-analysis of existing mobile mRNA datasets and examine the associated bioinformatic pipelines. Taking technological noise, biological variation, potential contamination and incomplete genome assemblies into account, we find that a high percentage of currently annotated graft-mobile transcripts are left without statistical support from available RNA-seq data. This meta-analysis challenges the findings of previous studies and current views on mRNA communication.

PMID:40240650 | DOI:10.1038/s41477-025-01979-x

Nat Rev Cancer. 2025 Apr 16. doi: 10.1038/s41568-025-00818-7. Online ahead of print.

NO ABSTRACT

PMID:40240643 | DOI:10.1038/s41568-025-00818-7

Cell Death Dis. 2025 Apr 16;16(1):307. doi: 10.1038/s41419-025-07623-y.

ABSTRACT

The von Hippel-Lindau (VHL) tumor suppressor is a substrate-defining component of E3 ubiquitin ligase complexes that target cellular substrates for proteasome-mediated degradation. VHL inactivation by mutation or transcriptional silencing is observed in most sporadic cases of clear cell renal cell carcinoma (ccRCC). VHL loss in ccRCC leads to constitutive stabilization of E3 ligase substrates, including hypoxia inducible factor α (HIFα). HIFα stabilization upon VHL loss is known to contribute to ccRCC development through transactivation of hypoxia-responsive genes. HIF-independent VHL targets have been implicated in oncogenesis, although those mechanisms are less well-defined than for HIFα. Using proximity labeling to identify proteasomal-sensitive VHL interactors, we identified retinoblastoma protein (pRb) as a novel substrate of VHL. Mechanistically, VHL interacts with pRb in a proteasomal-sensitive manner, promoting its ubiquitin-mediated degradation. Concordantly, VHL-inactivation results in pRb hyperstabilization. Functionally, loss of pRb in ccRCC led to increased cell death, transcriptional changes, and loss of oncogenic properties in vitro and in vivo. We also show that downstream transcriptional changes induced by pRb hyperstabilization may contribute to ccRCC tumor development. Together, our findings reveal a novel VHL-related pathway which can be therapeutically targeted to inhibit ccRCC tumor development.

PMID:40240354 | DOI:10.1038/s41419-025-07623-y

Trends Immunol. 2025 Apr 15:S1471-4906(25)00077-8. doi: 10.1016/j.it.2025.03.003. Online ahead of print.

ABSTRACT

The Molecular Mechanisms of Immune Cell Development and Function (MMICDF) meeting sponsored by the Federation of American Societies of Experimental Biology (FASEB) occupies a special niche because of its focus on the molecular mechanisms that underpin immunological processes. This biennial meeting with small groupings of participants and interactive nature has provided a forum for intense, informative, and influential scientific discussions. The meeting is unique for its focus on molecular mechanisms that control the exceptional processes of DNA recombination, somatic hypermutation (SHM), and gene expression during immune cell development, activation, and differentiation. The organizers of the foundational meeting reflect on the coalescence of scientific advances that catalyzed its origin, review meeting highlights to celebrate its 20th anniversary, and project into the future.

PMID:40240192 | DOI:10.1016/j.it.2025.03.003

Cell. 2025 Apr 14:S0092-8674(25)00346-0. doi: 10.1016/j.cell.2025.03.028. Online ahead of print.

ABSTRACT

How developmental signals program gene expression in space and time is still poorly understood. Here, we addressed this question for the plant master regulator, auxin. Transcriptional responses to auxin rely on a large multigenic transcription factor family, the auxin response factors (ARFs). We deconvoluted the complexity of ARF-regulated transcription using auxin-inducible synthetic promoters built from cis-element pair configurations differentially bound by ARFs. We demonstrate using cellular systems that ARF transcriptional properties are not only intrinsic but also depend on the cis-element pair configurations they bind to, thus identifying a bi-layer ARF/cis-element transcriptional code. Auxin-inducible synthetic promoters were expressed differentially in planta showing at single-cell resolution how this bi-layer code patterns transcriptional responses to auxin. Combining cis-element pair configurations in synthetic promoters created distinct patterns, demonstrating the combinatorial power of the auxin bi-layer code in generating diverse gene expression patterns that are not simply a direct translation of auxin distribution.

PMID:40239648 | DOI:10.1016/j.cell.2025.03.028

Cell. 2025 Apr 12:S0092-8674(25)00349-6. doi: 10.1016/j.cell.2025.03.031. Online ahead of print.

ABSTRACT

Polyglutamine (polyQ) expansion is associated with pathogenic protein aggregation in neurodegenerative disorders. However, long polyQ tracts are also found in many transcription factors (TFs), such as FOXP2, a TF implicated in human speech. Here, we explore how FOXP2 and other glutamine-rich TFs avoid unscheduled assembly. Throughout interphase, DNA binding, irrespective of sequence specificity, has a solubilizing effect. During mitosis, multiple phosphorylation events promote FOXP2's eviction from chromatin and supplant the solubilizing function of DNA. Further, human-specific amino acid substitutions linked to the evolution of speech map to a mitotic phospho-patch, the "EVO patch," and reduce the propensity of the human FOXP2 to assemble. Fusing the pathogenic form of Huntingtin to either a DNA-binding domain, a phosphomimetic variant of this EVO patch, or a negatively charged peptide is sufficient to diminish assembly formation, suggesting that hijacking mechanisms governing solubility of glutamine-rich TFs may offer new strategies for treatment of polyQ expansion diseases.

PMID:40239647 | DOI:10.1016/j.cell.2025.03.031

Cell Rep Med. 2025 Apr 15;6(4):102045. doi: 10.1016/j.xcrm.2025.102045.

ABSTRACT

We present the clinical results of a phase 2 trial combining neoadjuvant docetaxel, cisplatin, 5 Flourouracil, and the PD-L1 inhibitor avelumab in locally advanced gastro-esophageal adenocarcinoma (GEA). Fifty-one patients receive neoadjuvant therapy with 50 proceeding to surgery. Grade 3-4 adverse events occur in 40%; complete/major pathological response is found in 7/50 (14%) and 9/50 (18%), with 2-year disease-free survival of 67.5%. There is no correlation between tumor regression and PD-L1 or mismatch repair (MMR) status. Multiplex immunohistochemistry and longitudinal single-cell transcriptomic profiling reveal alterations in certain innate immune cell populations, particularly noting an M2-tumor-associated macrophage (M2-TAM) proliferation in non-responding tumors. These findings describe the effective nature of this treatment regimen for GEA and reveal associated features of the inflammatory milieux associated with response to chemo-immunotherapy. The specific character of the inflammatory environment in non-responders may, in the future, help personalize treatment. This study was registered at ClinicalTrials.gov (NCT03288350).

PMID:40239627 | DOI:10.1016/j.xcrm.2025.102045