Search Results (36)

Bt Cry toxins remain the cornerstone of transgenic crop protection against Lepidopteran pests, yet field-evolved resistance, particularly in invasive species such as Spodoptera frugiperda and Helicoverpa armigera, can threaten their long-term efficacy. This review presents a comprehensive and unified mechanistic framework that synthesizes current understanding of Bt Cry toxin modes of action and the complex, multilayered regulatory mechanisms of field-evolved resistance. Beyond the classical pore-formation model, emerging evidence highlights signal transduction cascades, immune evasion via suppression of Toll/IMD pathways, and tripartite toxin–host–microbiota interactions that can dynamically modulate protoxin activation and receptor accessibility. Resistance arises from target-site alterations (e.g., ABCC2/ABCC3, Cadherin mutations), altered midgut protease profiles, enhanced immune regeneration, and microbiota-mediated detoxification, orchestrated by transcription factor networks (GATA, FoxA, FTZ-F1), constitutive MAPK hyperactivation (especially MAP4K4-driven cascades), along with preliminary emerging findings on non-coding RNA involvement. Countermeasures now integrate synergistic Cry/Vip pyramiding, CRISPR/Cas9-validated receptor knockouts revealing functional redundancy, Domain III chimerization (e.g., Cry1A.105), phage-assisted continuous evolution (PACE), and the emerging application of AlphaFold3 for structure-guided rational redesign of resistance-breaking variants. Future sustainability hinges on system-level integration of single-cell transcriptomics, midgut-specific CRISPR screens, microbiome engineering, and AI-accelerated protein design to preempt resistance trajectories and secure Bt biotechnology within integrated resistance and pest management frameworks. Full article

As the brain’s resident macrophages, microglia on the one side are increasingly recognized as essential players in discrete developmental stages, where immune, metabolic, and activity-derived signals are coordinately integrated to guide brain development. On the other side, the precise temporal and molecular coordination of microglial maturation is imperative for the structural and functional integrity of the developing central nervous system (CNS). In this review, we synthesize recent data that reposition microglia from a uniform population of immune sentinels to temporally programmed and regionally specialized regulators of circuit maturation. This involves dissecting the embryonic origins and migratory pathways of microglial progenitors in mouse and human systems and illustrating how gradual transcriptional and morphological maturation aligns the biology of microglia with progressive phases of neurogenesis, synaptic fine-tuning, myelination, and vascular stabilization. In addition, we discuss how individual gene mutations, inflammatory insults during perinatal life, and environmental disturbances intersect with these temporal programs to alter microglial phenotypes and compromise circuit formation. With a special emphasis on epilepsy and autism spectrum disorder, often sharing the common etiology, we illustrate how early malfunction of microglia may drive neural network dysfunction. Full article

Understanding how plants respond to water limitation is increasingly important under accelerating climate change. Lycoris aurea, a widely distributed ornamental and medicinal bulbous plant, frequently inhabits environments with fluctuating soil moisture, yet its molecular drought-response mechanisms remain largely unexplored. In this study, we investigated L. aurea growing under field-based, in situ soil moisture regimes, comparing low (~20% soil water content) and high (~40% soil water content) conditions. We combined soil property assessments with high-resolution transcriptomic and untargeted metabolomic profiling to characterize the adaptive responses of bulb tissues under contrasting soil water conditions. Although total nitrogen, phosphorus, and potassium levels were comparable across treatments, soil moisture, representing the primary contrasting field condition, and soil pH, a correlated environmental factor, were significantly associated with variation in gene expression and metabolite accumulation (p < 0.05, n = 3). Transcriptome analyses identified a total of 1034 differentially expressed genes enriched in pathways related to amino acid metabolism, cuticle formation, cell wall modification, and osmotic adjustment. Metabolomic analysis identified a total of 1867 differentially expressed metabolites belonging to carboxylic acids and prenol lipids, showing alterations involved in amino acids, lipids, phenolic acids, and alkaloids associated with osmoprotection, membrane stabilization, and structural reinforcement under low soil moisture. Pathway-based integration analysis highlighted four core pathways, including “alanine, aspartate and glutamate metabolism” (p = 0.00371) and “cutin, suberine and wax biosynthesis” (p = 0.00873), as central hubs linking transcriptional regulation with metabolic reconfiguration. Gene-metabolite-soil correlation networks further demonstrated that drought adaptation arises from tightly coordinated biochemical and structural adjustments rather than shifts in nutrient acquisition. Together, this species-specific study provides a comprehensive multi-omics framework for understanding drought tolerance in L. aurea, reveals key molecular targets associated with plant resilience, and offers potential targets and insights for the conservation of drought-resilient Lycoris cultivars. Full article

Potato (Solanum tuberosum) is one of the world’s most important food crops, with tuber sink strength and starch deposition determining yield, quality, and processing performance. While starch is the dominant carbohydrate reserve, its accumulation is tightly linked with protein metabolism. Patatin, the major soluble storage protein, constitutes up to 40% of total tuber protein. In addition to serving as a nitrogen and carbon reserve, patatin exhibits lipid acyl hydrolase (phospholipase A₂-like) activity, suggesting roles in membrane remodeling and stress signaling. This dual identity places patatin at the intersection of storage, metabolic regulation, and defense. A structured review of studies published between 1980 and 2025 was developed using PubMed, Web of Science, Frontiers, and MDPI databases. Prioritized research included molecular, physiological, and multi-omics analyses of patatin expression, regulation, and function under optimal and stress conditions. Evidence indicates that patatin contributes to carbon–nitrogen balance and sink strength by affecting sucrose import, vacuolar osmotic capacity, and starch biosynthesis. Under drought, salinity, and pathogen stress, patatin transcript levels, protein stability, and enzymatic activity shift, leading to reduced starch deposition, altered sugar accumulation, osmoprotection, and reallocation toward defense responses. Despite these insights, major knowledge gaps remain. These include isoform-specific roles, integration into sugar–hormone regulatory networks, and field-scale responses under fluctuating environments. Future progress will require integrated multi-omics, fluxomics, and proximity-labeling approaches, combined with CRISPR-based isoform editing and promoter engineering. Targeting patatin as both a biomarker and an engineering node offers opportunities to develop climate-ready potato cultivars with improved starch yield, tuber quality, and stress resilience. Full article

Glycation-induced modifications of extracellular matrix (ECM) proteins, including collagen, are increasingly recognized as critical modulators of cellular behavior, particularly in pathophysiological contexts such as aging and diabetes. While their impact on general cell adhesion has been explored, the specific consequences for mesenchymal stem cell (MSC) mechanotransduction remain poorly defined. In this study, we investigated the temporal and mechanistic aspects of adhesion and mechanosensitive signaling in adipose-derived MSCs (ADMSCs) cultured on native versus glycated collagen substrates. Our findings identify two temporally distinct adhesion mechanisms: an initial pathway mediated by the receptor for advanced glycation end-products (RAGE), which is activated within the first 30 min following substrate engagement, and a later-stage adhesion process predominantly governed by integrins. Immunofluorescence analysis demonstrated maximal nuclear localization of YAP/TAZ transcriptional regulators during the initial adhesion phase, coinciding with RAGE engagement. This nuclear enrichment was progressively attenuated as integrin-mediated focal adhesions matured, suggesting a dynamic shift in receptor usage and mechanotransductive signaling. Interestingly, glycated collagen substrates accelerated early cell attachment but impaired focal adhesion maturation, suggesting a disruption in integrin engagement. Endogenous collagen synthesis was consistently detected at all examined time points (30 min, 2 h, and 5 h), suggesting a constitutive biosynthetic activity that remains sensitive to the glycation state of the substrate. Atomic force microscopy (AFM) demonstrated that glycation disrupts collagen fibrillogenesis: while native collagen forms a well-organized network of long, interconnected fibrils, GL-1 substrates (glycated for 1 day) displayed sparse and disordered fibrillary structures, whereas GL-5 substrates (5-day glycation) exhibited partial restoration of fibrillar organization. These matrix alterations were closely associated with changes in adhesion kinetics and mechanotransduction profiles. Taken together, our findings demonstrate that collagen glycation modulates both adhesion dynamics and mechanosensitive signaling of MSCs through a dual-receptor mechanism. These insights have significant implications for the design of regenerative therapies targeting aged or metabolically compromised tissues, where ECM glycation is prevalent. Full article

The way in which Aquaporin-4 (AQP4) is localized on the astrocytes’ surface—i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels—represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood–brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity—a loss in the organization of AQP4 channels to the perivascular membrane—is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4—such as dystrophin–syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators—and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood–brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the “fluidic connectome”, and highlight its importance in maintaining overall brain health across disease states. Full article

The process of aging is fundamentally driven by genomic instability and the accumulation of DNA damage, which progressively impair cellular and tissue function. In order to counteract these challenges, cells rely on the DNA damage response (DDR), a multilayered signaling and repair network that preserves genomic integrity and sustains homeostasis. Within this framework, nucleases and helicases have pivotal and complementary roles by remodeling aberrant DNA structures, generating accessible repair intermediates, and determining whether a cell achieves faithful repair, undergoes apoptosis, or enters senescence. Defects in these enzymes are exemplified in human progeroid syndromes, where inherited mutations lead to premature aging phenotypes. This phenomenon is also replicated in genetically engineered mouse models that exhibit tissue degeneration, stem cell exhaustion, and metabolic dysfunction. Beyond their canonical repair functions, helicases and nucleases also interface with the epigenome, as DNA damage-induced chromatin remodeling alters enzyme accessibility, disrupts transcriptional regulation, and drives progressive epigenetic drift and chronic inflammatory signaling. Moreover, their dysfunction accelerates the exhaustion of adult stem cell populations, such as hematopoietic, neural, and mesenchymal stem cells. As a result, tissue regeneration is undermined, establishing a self-perpetuating cycle of senescence, impaired repair, and organismal aging. Current research is focused on developing therapeutic strategies that target the DDR–aging axis on several fronts: by directly modulating repair pathways, by regulating the downstream consequences of senescence, or by preventing DNA damage from accumulating upstream. Taken together, evidence from human disease, animal models, molecular studies, and pharmacological interventions demonstrates that nucleases and helicases are not only essential for genome maintenance but also decisive in shaping aging trajectories. This provides valuable knowledge into how molecular repair pathways influence organismal longevity and age-related diseases. Full article

Numerous infants have been conceived by in vitro fertilization (IVF) and other assisted reproductive technologies (ART). Increasing evidence indicates that these approaches induce minor alterations in molecules during the initial phases of embryogenesis. This narrative review examines the molecular pathophysiology of embryonic cardiogenesis in the context of assisted reproductive technology, emphasizing transcriptional and epigenetic regulation. Essential transcription factors for cardiac development, including NKX2-5, GATA4, TBX5, ISL1, MEF2C, and HAND1/2, play a crucial role in mesodermal specification, heart tube formation, and chamber morphogenesis. Animal models and human preimplantation embryos have demonstrated that ART-related procedures, including gamete micromanipulation, supraphysiological hormone exposure, and extended in vitro culture, can alter the expression or epigenetic programming of these genes. Subsequent to ART, researchers have identified anomalous patterns of DNA methylation, alterations in histones, and modifications in chromatin accessibility in cardiogenic loci. These alterations indicate that errors occurred during the initial reprogramming process, potentially resulting in structural congenital heart abnormalities (CHDs) or modifications in cardiac function later in life. Analysis of the placental epigenome in babies conceived using assisted reproductive technology reveals that imprinted and developmental genes critical for cardiac development remain dysfunctional. This review proposes a mechanistic theory about the potential subtle alterations in the cardiogenic gene network induced by ART, synthesizing findings from molecular embryology, transcriptomics, and epigenomics. Understanding these molecular issues is crucial not only for enhancing ART protocols but also for evaluating the cardiovascular risk of children conceived by ART postnatally and for early intervention. Full article

Mechanical and contractile forces in the vascular wall regulate smooth muscle cell migration. We previously demonstrated the presence of C3 complement products in atherosclerotic lesions of human aortas and showed that that C3-derived fragments promote key cellular processes, such as actin cytoskeleton organization and cell migration, in lipid-loaded human vascular smooth muscle cells (hVSMCs). In the present study, we aimed to investigate gene expression profiles related to cytoskeletal remodeling and cell adhesion in migrating hVSMCs with a particular focus on modulatory effect of the C3 complement pathway on these processes. We analyzed gene expression in migrating and non-migrating hVSMCs using real-time PCR and in silico network analysis. Additionally, we investigated cytoskeletal remodeling through Western blotting and confocal microscopy. PCR profiling revealed 30 genes with significantly altered expression in migrating hVSMCs compared to non-migrating control cells. In silico analysis identified six of these genes—PXN, AKT1, RHOA, VCL, CTNNB1, and FN1—as being associated with cytoskeletal remodeling and focal adhesion, with PXN occupying a central position in the interaction network. PXN expression was reduced at both the transcript and protein levels and showed altered subcellular localization in migrating lipid-loaded hVSMCs. Protein–protein interaction analysis using STRING predicted an association between PXN and the integrin complex αMβ2 (comprising ITGAM (CD11b) and ITGB2 (CD18)), which functions as receptors for the iC3b complement fragment. Confocal imaging of cell adhesion structures revealed that lipid-loaded hVSMCs stimulated with iC3b displayed a more diffuse PXN distribution and significantly increased PXN–F-actin colocalization in active cytoplasmic regions compared to lipid-loaded control cells. PXN–F-actin colocalization increased from 1.26% to 19.68%. Subcellular fractionation further confirmed enhanced PXN enrichment in the membrane fraction, with no significant changes observed in the cytosolic or cytoskeletal compartments. In conclusion, iC3b-mediated molecular signaling in lipid-loaded hVSMCs alters PXN distribution and enhances cytoskeletal remodeling, revealing novel molecular interactions in vascular remodeling and the progression of atherosclerotic lesions. Full article

During fruit ripening in Capsicum species, substantial amounts of carotenoids accumulate in the pericarp. While the carotenoid biosynthesis pathway in Capsicum species has been extensively investigated from various angles, the transcriptional regulation of genes encoding carotenoid biosynthetic enzymes remains less understood in this non-climacteric horticultural crop compared to tomato, a climacteric fruit. In the present study, we investigated the function of the NAM, ATAF1/2 or CUC2 81 (CaNAC81) transcription factor gene. This gene was selected through RNA-Seq co-expression analysis based on the correlation between expressed transcription factor gene profiles and those of carotenoid structural genes. To determine its role in regulating the expression of biosynthetic-related carotenogenic genes, we performed Virus-Induced Gene Silencing (VIGS) assays in the Serrano-type C. annuum ‘Tampiqueño 74’. Fruits from plants infected with a pTRV2:CaNAC81 construct (silenced fruits) exhibited altered carotenoid pigmentation accumulation, manifested as yellow-orange spots, in contrast to fruits from non-agroinfected controls (NTC) and fruits from plants infected with the empty TRV2 construct (red fruits). Quantitative real-time PCR (qPCR) assays confirmed decreased transcript levels of CaNAC81 in fruits displaying altered pigmentation, along with reduced transcription of the PSY gene, which encodes the carotenoid biosynthetic enzyme phytoene synthase (PSY). High-performance liquid chromatography (HPLC) analysis revealed a distinct carotenoid pigment accumulation pattern in fruits from plants showing silencing symptoms, characterized by low concentrations of capsanthin and zeaxanthin and trace amounts of capsorubin, compared to control plants (NTC). These findings suggest the involvement of CaNAC81 in the regulatory network of the carotenoid biosynthetic pathway in chili pepper fruits. Full article

Cardiac cachexia (CC) is an advanced stage of heart failure (HF) characterized by structural and functional abnormalities in skeletal muscle, leading to muscle loss. Aerobic training provides benefits; however, the underlying molecular mechanisms remain poorly understood. This study aimed to investigate the therapeutic effects of aerobic training on transcriptomic alterations associated with disease progression in cachectic skeletal muscle. HF was induced in male Wistar rats by a single monocrotaline injection (60 mg/Kg). Aerobic training consisted of 30 min treadmill running at ~55% of maximal capacity, 5×/week for 4 weeks. Assessments included body mass, right ventricle mass, skeletal muscle fiber size and exercise tolerance. RNA-seq analysis was performed on the medial gastrocnemius muscle. Sedentary cachectic rats exhibited 114 differentially expressed genes (DEGs) while exercised cachectic rats had only 18 DEGs. Enrichment pathways analyses and weighted gene co-expression network analysis (WGCNA) identified potential key genes involved in disrupted lipid metabolism in sedentary cachectic rats, which were not observed in the exercised cachectic rats. Validation of DEGs related to lipid metabolism confirmed that Dgat2 gene expression was modulated by aerobic training in CC rats. These findings suggest that aerobic training mitigates transcriptional alterations related to lipid metabolism in rats with CC, highlighting its therapeutic potential. Full article

In eukaryotes, the mitogen-activated protein kinase (MAPK) cascade pathway is a highly conserved cell signaling mechanism that is essential for stress response, growth, and development. MAPK cascade genes have currently been identified and characterized in a wide range of fungi, although they have not been fully understood in early divergent fungal lineages like the Mucoromycota, which contains Mucoromycotina, Glomeromycotina, and Mortierellomycotina. In this study, a genome-wide investigation of Blakeslea trispora (Mucorales, Choanephoraceae) revealed a total of 19 MAPK cascade genes, including 9 BtMAPKKKs, 4 BtMAPKKs, and 6 BtMAPKs genes. Using phylogenetic analysis, it was found that the kinase domain sequences and motif composition of the three MAPK, MAPKK, and MAPKKK lineages are substantially conserved in fungi. Whole genome duplication analysis indicated that B. trispora has four and nine duplication pairs in the MAPK and MAPKKK genes, respectively, which are expanded by segmental replication events. BtHog2, the orthologous protein of Hog1, exhibits a substantial rise in transcription levels under blue light irradiation, indicating its function in light signal response and transduction. Several sets of interacting protein pairs were found using molecular docking analysis and yeast two-hybrid assay, providing a comprehensive MAPK cascade signaling network in B. trispore. Furthermore, MAPK cascade proteins show varying transcription levels in response to blue light and sex hormone stimulation, as well as variable treatment duration. BtMAPKKK9 and BtBck1 are strongly induced during sexual interaction, indicating their involvement in the response to trisporic acid and the subsequent alterations in hyphal cell wall structure. These findings shed light on the evolution of MAPK cascade genes and the functional mechanisms underlying MAPK cascade genes in response to light and sex hormone signaling pathways in B. trispore. Full article

Plants continuously adapt to their environments by responding to various intrinsic and extrinsic signals. They face numerous biotic and abiotic stresses such as extreme temperatures, drought, or pathogens, requiring complex regulatory mechanisms to control gene activity and adapt their proteome for survival. Epigenetic regulation plays a crucial role in these adaptations, potentially leading to both heritable and non-heritable changes across generations. This process enables plants to adjust their gene expression profiles and acclimate effectively. It is also vital for plant development and productivity, affecting growth, yield, and seed quality, and enabling plants to “remember” environmental stimuli and adapt accordingly. Key epigenetic mechanisms that play significant roles include DNA methylation, histone modification, and ubiquitin ligase complex activity. These processes, which have been extensively studied in the last two decades, have led to a better understanding of the underlying mechanisms and expanded the potential for improving agriculturally and economically important plant traits. DNA methylation is a fundamental process that regulates gene expression by altering chromatin structure. The addition of methyl groups to cytosines by DNA methylases leads to gene suppression, whereas DNA demethylases reverse this effect. Histone modifications, on the other hand, collectively referred to as the “histone code”, influence chromatin structure and gene activity by promoting either gene transcription or gene silencing. These modifications are either recognized, added, or removed by a variety of enzymes that act practically as an environmental memory, having a significant impact on plant development and the responses of plants to environmental stimuli. Finally, ubiquitin ligase complexes, which tag specific histones or regulatory proteins with ubiquitin, are also crucial in plant epigenetic regulation. These complexes are involved in protein degradation and play important roles in regulating various cellular activities. The intricate interplay between DNA methylation, histone modifications, and ubiquitin ligases adds complexity to our understanding of epigenetic regulation. These mechanisms collectively control gene expression, generating a complex and branching network of interdependent regulatory pathways. A deeper understanding of this complex network that helps plants adapt to environmental changes and stressful conditions will provide valuable insights into the regulatory mechanisms involved. This knowledge could pave the way for new biotechnological approaches and plant breeding strategies aimed at enhancing crop resilience, productivity, and sustainable agriculture. Full article

Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate for the lack of a systematic interpretation of the functional characterization and regulatory mechanisms of TCNE spatiotemporal activities, we developed a flexible pipeline, called captureTCNE, to depict the landscape of TCNEs and applied it to our breast cancer cohort (SEU-BRCA). Meanwhile, we investigated the genome-wide characteristics of TCNEs and unraveled that TCNEs harbor enhancer-like chromatin signatures as well as participate in the transcriptional machinery to regulate essential genes or architect biological regulatory networks of breast cancer. Specifically, the TCNE transcripts could recruit RBPs, such as ENOX1 and PTBP1, which are involved in gene expression regulation, to participate in the formation of regulatory networks and the association with altered splicing patterns. In particular, the presence of a non-classical secondary structure, called RNA G-quadruplex, on TCNE transcripts contributed to the recruitment of RBPs associated with subtype-specific transcriptional processes related to the estrogen response in breast cancer. Ultimately, we also analyzed the mutational signatures of variant-containing TCNEs and discerned twenty-one genes as essential components of the regulatory mechanism of TCNEs in breast cancer. Our study provides an effective TCNE identification pipeline and insights into the regulatory mechanisms of TCNEs in breast cancer, contributing to further knowledge of TCNEs and the emergence of innovative therapeutic strategies for breast cancer. Full article

The interplay between cancer and the immune system has captivated researchers for a long time. Recent developments in cancer immunotherapy have substantiated this interest with a significant benefit to cancer patients. Tumor and immune cells are regulated via a wide range of molecular mechanisms involving intricate transcriptional and epigenetic networks. Epigenetic processes influence chromatin structure and accessibility, thus governing gene expression, replication, and DNA damage repair. However, aberrations within epigenetic signatures are frequently observed in cancer. One of the key epigenetic marks is the trimethylation of histone 3 at lysine 9 (H3K9me3), confined mainly within constitutive heterochromatin to suppress DNA accessibility. It is deposited at repetitive elements, centromeric and telomeric loci, as well as at the promoters of various genes. Dysregulated H3K9me3 deposition disrupts multiple pathways, including immune signaling. Consequently, altered H3K9me3 dynamics may modify the efficacy of immunotherapy. Indeed, growing evidence highlights the pivotal roles of various proteins mediating H3K9me3 deposition (SETDB1/2, SUV39H1/2), erasure (KDM3, KDM4 families, KDM7B, LSD1) and interpretation (HP1 proteins, KAP1, CHD4, CDYL, UHRF1) in modulating immunotherapy effectiveness. Here, we review the existing literature to synthesize the available information on the influence of these H3K9me3 writers, erasers, and readers on the response to immunotherapy. Full article