Search Results (376)

Background/Objectives: The rise of immune escape variants of the SARS-CoV-2 virus has prompted the development of vaccines based on the variant’s spike antigen sequence. Since variant-specific SARS-CoV-2 vaccines are mostly administered as boosters to individuals previously vaccinated with reference (Ref.) strain-based vaccines, a better understanding of their immunogenicity in this context is essential. Protein subunit vaccines have a well-established track record of safety. Herein, we assessed the ability of variant-specific protein subunit vaccine formulations to boost pre-existing Ref. strain-specific immune responses compared to boosting with a Ref. strain-specific formulation in young and aged female Balb/c mice. Methods: Following a priming vaccination series with Ref. spike protein adjuvanted with sulfated lactosyl archaeol (SLA) archaeosomes on days 0 and 21, immune responses were evaluated in young and aged female Balb/c mice. On day 91, mice received a third immunization with Ref., Beta, or Delta spike protein formulations, with or without SLA archaeosomes. Antibody titers, neutralization activity, and cellular immune responses were measured to assess the impact of the booster formulation. Results: Aged mice exhibited lower antibody titers throughout the study and a decline over time compared to young mice. After a third immunization, responses were boosted by all vaccine formulations (Ref., Beta, or Delta), with or without adjuvant. However, variant-specific antigen formulations did not overcome immune imprinting from the priming series or increase neutralization activity against the corresponding SARS-CoV-2 variants in either age group. Conclusions: Variant-specific protein subunit vaccines enhanced immune responses but did not overcome immune imprinting induced by the Ref. strain’s priming. The inclusion of SLA archaeosomes improved cellular immunity, supporting their potential role in optimizing booster vaccine performance, particularly in aged populations. Full article

Multiple sclerosis (MS), the most prevalent chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults, exhibits marked sexual dimorphism, with a 3:1 female-to-male ratio, but more severe symptoms and greater neurological damage in males. Increasing attention has focused on identifying circulating molecules that reflect inflammatory activity within the central nervous system and could clarify the mechanisms underlying MS. Pleiotrophin (PTN), a cytokine implicated in autoimmune and neurological diseases, is significantly elevated in patients with relapsing-remitting MS (RRMS). To explore the potential contribution of PTN and its receptors to neuroinflammatory signaling, we quantified the mRNA expression of PTN receptors in peripheral blood mononuclear cells from RRMS patients compared to untreated RRMS patients and healthy control subjects. We further performed an in silico molecular docking and molecular dynamics analysis to assess the possible functional significance of PTN-receptor interactions. Our results show a significant overexpression of integrin subunit beta-3 (ITGB3) mRNA in peripheral blood mononuclear cells from RRMS patients compared to healthy control subjects. Molecular docking shows that PTN could binds to the metal ion-dependent adhesion site domain of ITGB3 via Mg²⁺/Ca²⁺-mediated stabilization and has a higher binding affinity than fibrinogen, the canonical endogenous ligand. These findings suggest that ITGB3 could be a dynamically regulated integrin receptor in RRMS that may participate in PTN-driven neuroinflammatory pathways in peripheral blood immune cells, influenced by disease stage, sex, and immunotherapy. While our results support the biological plausibility of PTN–ITGB3 engagement, they remain hypothesis-generating and require functional validation. The integration of molecular expression data and computational modeling underscores the potential involvement of ITGB3 as a possible participant in MS and warrants further investigation of its clinical and mechanistic role. Full article

Background: Acute pancreatitis is a significant global disease. This study investigated the phytochemical composition and potential protective effects of Equisetum arvense L. (horsetail) ethanol extract and Olea europaea L. (olive leaves) aqueous extract against metronidazole (MTZ)-induced pancreatic damage in rats. Materials and Methods: Rats were randomly divided into six groups: Group I (control) received saline; Group II (Metronidazole) received only MTZ (400 mg/kg). Group III (Equisetum arvense group) received E. arvense 100 mg/kg. Group IV (Olea europaea) received 400 mg/kg of O. europaea. Group V (MTZ + E. arvense) received both MTZ (400 mg/kg) and E. arvense (100 mg/kg). Group VI (MTZ + O. europaea) received MTZ (400 mg/kg) and O. europaea (400 mg/kg). All treatments were delivered daily via the oral route. After 60 days, serum amylase, lipase, protease, and glucose levels, oxidative parameters “malondialdehyde (MDA), catalase (CAT), mRNA relative expression of pancreatic Pik3ca (phosphatidylinosi-tol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), AKT (AKT Serine/Threonine Kinase 1), Nrf-2 (Nuclear factor, erythroid 2-like 2), TNFα (tumor necrosis factor alpha), and IL-1β (interleukin-1 beta genes, an apoptotic marker “caspase-3,” and histopathological changes were estimated. Results: HPLC analysis revealed that horsetail extract contained caffeic acid, catechin, rutin, and kaempferol, while olive leaf extract was dominated by oleuropein. MTZ administration significantly elevated serum levels of pancreatic enzymes (lipase, amylase, and protease) and glucose and increased oxidative stress markers, such as MDA, while reducing catalase (CAT) activity. Co-treatment with MTZ and horsetail, or MTZ and olive extracts, mitigated these effects, especially horsetail, which restored CAT levels and reduced MDA concentrations. qPCR analysis showed MTZ upregulated inflammatory genes (TNFα, IL-1β) and downregulated antioxidant and survival-related genes (Pik3ca, AKT, Nrf-2). Horsetail co-treatment significantly reversed these gene expression patterns. Histopathological and immunohistochemical analyses confirmed MTZ-induced pancreatic tissue degeneration and increased cleaved caspase-3 expression, both of which were notably alleviated by horsetail extract. Conclusions: These findings highlight the superior protective efficacy of Equisetum arvense over Olea europaea in ameliorating MTZ-induced pancreatic toxicity, potentially through anti-inflammatory, antioxidant, and anti-apoptotic mechanisms. Full article

African swine fever virus (ASFV) causes a highly fatal disease in domestic pigs, resulting in substantial economic losses to the global swine industry. Vaccine development continues to be hindered by limited characterization of viral proteins and their functional redundancies. In this study, we employ combined experimental and computational approaches to characterize the ASFV I73R protein (pI73R), which contains a Z-DNA binding domain and plays a critical role in ASFV virulence and pathogenesis. We demonstrate that pI73R shares significant structural similarity with transcription factors of the forkhead box (FOX) protein family. Overexpression of pI73R results in downregulation of Crooked neck-like protein 1 (CRNKL1), a core spliceosome component, suggesting a potential mechanism by which pI73R modulates host protein synthesis. Using high-resolution mass spectrometry, we map the pI73R interactome and identify the host protein Guanine nucleotide-binding protein subunit beta-1 (GNB1) as a novel direct interactor of pI73R which may facilitate its nuclear transport. Furthermore, we show that pI73R exhibits consistent oligomerization and expression across different ASFV genotypes, highlighting its functional importance. Taken together, these results provide new insights into pI73R function, ASFV–host dynamics, and offer promising directions for antiviral strategy development. Full article

Background and Objectives: There is adherence to a healthy Mediterranean diet (MedDiet), but adherence varies widely. Precision nutrition is increasingly interested in individual characteristics influencing diet adherence, but few studies have examined personality traits. Our main aim was to investigate the association between personality traits and MedDiet adherence. Our secondary aims were to explore genome-wide genetic variants associated with neuroticism, including replication of previous findings, as well as to explore gene–MedDiet interactions. Methods: We analyzed participants (aged 55–75) in the PREDIMED-Plus-Valencia study and measured clinical, lifestyle, and genetic factors. The Eysenck Personality Questionnaire-Revised (EPQ-R) was used to measure neuroticism, psychoticism, and extraversion. Genotyping was undertaken, and associations with candidate SNPs, genome-wide association studies (GWAS), genetic risk scores (GRS), and gene–MedDiet interactions were explored. Results: Neuroticism was inversely (beta = −0.09; p = 0.001) associated with adherence to the Mediterranean diet (MEDAS-17). Likewise, the probability of low MedDiet adherence increased neuroticism (OR: 1.27; 95% CI: 1.02–1.60; p = 0.031 per SD). In the GWAS for this trait, several SNPs surpassed the suggestive level of statistical significance. The most strongly associated was rs10181407-NDUFA10 (NADH dehydrogenase 1 alpha subcomplex subunit 10) (beta = −2.39; p = 2.70 × 10⁻⁶). The GRS for neuroticism was significantly associated with MedDiet adherence (beta = −0.18; p = 0.020), increasing the causality level. We replicated some candidate SNPs, and among them, the rs2243873-EHMT2 (euchromatic histone lysine methyltransferase 2) gene. The analysis of gene–MedDiet interactions revealed the role of these dietary modulations. Conclusions: Neuroticism was the personality trait most inversely associated with MedDiet adherence, suggesting its integration in precision nutrition analysis. Moreover, neuroticism-related genetics and MedDiet modulations will also be important. Full article

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study may indicate a positive outcome but have too small of a sampling population to adequately evaluate unwanted outcomes. Prader–Willi syndrome (PWS) is one such genetic disorder with varied subtypes and heterogeneity, where little progress has been made in treatment discoveries. Recently, the FDA approved diazoxide choline for treating key features of hyperphagia and obesity associated with PWS based on clinical trial experience. Diazoxide choline activates the ATP-sensitive potassium channel (KATP) of pancreatic beta cells, inhibiting the release of insulin. One of the subunits of KATP is the protein Kir6.2, the gene product of KCNJ11. Methods: Web-based programs and datasets were used to study the gene and protein functional enrichments of Kir6.2 and KCNJ11, including shared gene and/or protein–protein interactions, and biological processes and functions. Results: Four essential domains of related functions were identified: (1) apoptosis, protein degradation, and inflammation; (2) the coupling of G proteins needed for KATP channel activation; (3) glucose metabolism and control; and (4) the maintenance of intracellular ionic homeostasis. Conclusions: Cellular metabolism in the pancreas is linked to membrane excitability by KATP, which regulates insulin production, energy production and storage, appetite regulation, and fatty acid synthesis. As such, diazoxide choline may influence several biological systems beyond pancreatic and metabolic functions. Full article

Eleutheroside E (EE), a natural compound, shows promise in mitigating cellular senescence—a key factor in skin aging—though its mechanisms remain incompletely understood. This study integrated network pharmacology, molecular docking, and cellular experiments to explore the protective effects and mechanistic basis of EE against D-galactose (D-gal)-induced senescence in human skin fibroblasts (HSFs). Network pharmacology analyses suggested EE’s involvement in inflammation-related pathways, especially phosphatidylinositol 3-kinase and protein kinase B (PI3K-AKT) and hypoxia-inducible factor 1 (HIF-1) signaling, which were corroborated by molecular docking revealing strong binding affinities between EE and key targets such as hypoxia-inducible factor 1-alpha (HIF1A), AKT serine/threonine kinase 1 (AKT1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PI3Kγ), and interleukin-6 (IL-6). Cellular assays showed that EE markedly lowered oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), reduced senescence-associated beta-galactosidase (SA-β-gal) activity, and boosted antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). Additionally, EE dose-dependently inhibited apoptosis and downregulated PI3K/AKT phosphorylation as well as the B-cell lymphoma 2-associated X protein/B-cell lymphoma-2 (Bax/Bcl-2) ratio. These findings suggest that EE alleviates cellular senescence in HSFs mainly via the PI3K/AKT pathway by attenuating oxidative stress and apoptosis, highlighting its potential as a therapeutic agent for anti-aging strategies. Full article

Background/Objectives: Identifying novel targets to treat gastric cancer (GC) has become a focus of research in recent years. Our accelerated Helicobacter-induced gastric cancer mouse model allowed us to identify several differentially expressed genes (DEGs), including Psmb8 (proteasome subunit beta type 8, also called Lmp7), which was also found to be elevated in GC patient samples. PSMB8 encodes one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. Methods: We identified carfilzomib from a public database as a potential drug targeting PSMB8; it effectively halts immunoproteasome activity, leading to apoptosis. We tested carfilzomib’s efficacy against gastric cancer by subcutaneously implanting nude mice with human gastric epithelial-derived tumors and treating them with carfilzomib, either alone or in combination with 5-fluorouracil (5-FU), a standard-of-care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. Results: We observed that carfilzomib retarded tumor growth, inhibited cell proliferation, and induced apoptosis. Conclusions: These results strongly suggest that PSMB8 is a suitable candidate for targeted therapy. Moreover, with carfilzomib having robust anti-tumor activity, it has potential as a treatment option for cancers where high levels of PSMB8 are associated with poor overall survival. Full article

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperactivation and dysregulated cytokine signaling, with nuclear factor kappa B (NF-κB), a master transcription factor that regulates immune and inflammatory gene expression, playing a central role. Adalimumab, a monoclonal antibody that inhibits tumor necrosis factor alpha (TNF-α), is widely used in psoriasis therapy, yet its molecular effects on NF-κB-associated genes and microRNAs (miRNAs) in keratinocytes remain insufficiently defined. In this study, immortalized human keratinocytes (HaCaT cells) were exposed to lipopolysaccharide (LPS) to induce inflammatory stress and treated with adalimumab for 2, 8, and 24 h. Transcriptome-wide profiling was performed using messenger RNA (mRNA) and miRNA microarrays, followed by validation with reverse transcription quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Bioinformatic analyses included prediction of miRNA–mRNA interactions, construction of protein–protein interaction (PPI) networks, and gene ontology (GO) enrichment. Adalimumab reversed LPS-induced upregulation of NF-κB-associated genes, including inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB), interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 2 (TRAF2), mitogen-activated protein kinase kinase kinase 7 (MAP3K7), and TNF alpha-induced protein 3 (TNFAIP3), with concordant changes observed at the protein level. Several regulatory miRNAs, notably miR-1297, miR-30a, miR-95-5p, miR-125b, and miR-4329, showed reciprocal expression changes consistent with anti-inflammatory activity. STRING analysis identified IKBKB as a central hub in the PPI network, while GO enrichment highlighted immune regulation, apoptosis, and NF-κB signaling. These findings demonstrate that adalimumab modulates NF-κB activity in keratinocytes through coordinated regulation of gene, protein, and miRNA expression, providing mechanistic insight into TNF-α blockade in psoriasis. Full article

The fruiting stage of soybean (Glycine max L.) is critical for determining both its yield and quality, thereby influencing global production. While some studies have provided partial explanations for the occurrence of Fusarium species on soybean seeds and pods, the fungal diversity affecting soybean pods in Sichuan Province, a major soybean cultivation region in Southwestern China, remains inadequately understood. In this study, 182 infected pods were collected from a maize–soybean relay strip intercropping system. A total of 10 distinct pod-infecting fungal genera (132 isolates) were identified, and their pathogenic potential on soybean seeds and pods was evaluated. Using morphological characteristics and DNA barcode markers, we identified 43 Fusarium isolates belonging to 8 species, including F. verticillioides, F. incarnatum, F. equiseti, F. proliferatum, F. fujikuroi, F. oxysporum, F. chlamydosporum, and F. acutatum through the analysis of the translation elongation factor gene (EF1-α) and RNA polymerases II second largest subunit (RPB2) gene. Multi-locus phylogenetic analysis, incorporating the Internal Transcribed Spacer (rDNA ITS), β-tubulin (β-tubulin), Glyceraldehyde 3-phosphate dehydrogenase (GADPH), Chitin Synthase 1 (CHS-1), Actin (ACT), Beta-tubulin II (TUB2), and Calmodulin (CAL) genes distinguished 37 isolates as 6 Colletotrichum species, including C. truncatum, C. karstii, C. cliviicola, C. plurivorum, C. boninense, and C. fructicola. Among these, F. proliferatum and C. fructicola were the most dominant species, representing 20.93% and 21.62% of the isolation frequency, respectively. Pathogenicity assays revealed significant damage from both Fusarium and Colletotrichum isolates on soybean pods and seeds, with varying isolation frequencies. Of these, F. proliferatum, F. acutatum, and F. verticillioides caused the most severe symptoms. Similarly, within Colletotrichum genus, C. fructicola was the most pathogenic, followed by C. truncatum, C. karstii, C. cliviicola, C. plurivorum, and C. boninense. Notably, F. acutatum, C. cliviicola, C. boninense, and C. fructicola were identified for the first time as pathogens of soybean pods under the maize–soybean strip intercropping system in Southwestern China. These findings highlight emerging virulent pathogens responsible for soybean pod decay and provide a valuable foundation for understanding the pathogen population during the later growth stages of soybean. Full article

Agrocybe chaxingu is a commercially important edible mushroom in China, valued for its rich bioactive compounds and distinctive umami flavor. In recent years, frequent disease outbreaks have severely limited production, as many pathogens spread rapidly and are difficult to control, posing a significant threat to the sustainable development of the industry. In this study, a systematic disease survey across major A. chaxingu cultivation areas in Jiangxi Province led to the isolation and identification of 17 potential fungal pathogens and 2 potential myxomycete pathogens using combined morphological characterization and multilocus phylogenetic analyses including the internal transcribed spacer (ITS) region, 28S large subunit ribosomal RNA (LSU), translation elongation factor (tef1), RNA polymerase largest subunit (rpb1), RNA polymerase second largest subunit (rpb2), Histone (H3), Beta tubulin (tub2), and 18S ribosomal RNA (18S rRNA). Among the identified diseases, white slime disease showed the highest incidence (17.3%) and was attributed to the slime mold Fuligo gyrosa, with pathogenicity confirmed according to Koch’s postulates. F. gyrosa proved highly virulent to both fruiting bodies and mycelia, enveloping host mycelium via plasmodial expansion, inhibiting growth, inducing structural rupture, and causing progressive degradation. Infection was accompanied by the deposition of characteristic stress-related pigments in the mycelium. This study provides the first detailed characterization of F. gyrosa infection dynamics in A. chaxingu mycelium. These findings provide new insights into the myxomycete pathogenesis in edible fungi and provide a foundation for the accurate diagnosis, targeted prevention, and sustainable management of diseases in A. chaxingu cultivation. Full article

Objectives: Retinitis pigmentosa (RP) is commonly initiated by rod photoreceptor degeneration due to genetic mutations, followed by secondary cone loss and progressive blindness. Preserving rod function during the earlier stages of RP is a key therapeutic goal, as rod survival supports cone maintenance and delays vision loss. In this study, we investigated the therapeutic potential of transient knockdown of retinoid-related orphan receptor beta (RORB) using a cell-penetrating asymmetric small interfering RNA (cp-asiRORB) in Rho^P23H mice, a model of autosomal dominant RP. While the role of RORB in the adult retina remains unclear, prior studies of related nuclear receptors suggest potential involvement in proteostasis. Based on this, we hypothesized that persistent RORB expression may influence photoreceptor homeostasis under degenerative stress. Methods: We first optimized the cp-asiRORB design to enhance gene silencing and cellular uptake. In vitro studies were conducted under proteotoxic stress. In vivo studies involved intravitreal administration of cp-asiRORB in Rho^P23H mice. Furthermore, single-cell RNA sequencing of rod photoreceptors was performed. Results: In vitro studies demonstrated that RORB knockdown improved cell viability, reduced apoptosis, and diminished aggresome formation under proteotoxic stress. Intravitreal administration of cp-asiRORB in Rho^P23H mice effectively reduced RORB expression in the retina, leading to improved photoreceptor survival and preserved visual function. Single-cell RNA sequencing revealed upregulation of proteasomal subunit genes in cp-asiRORB-treated eyes, indicating enhanced proteostasis. Conclusions: Together, these results demonstrate that transient suppression of RORB mitigates proteotoxic stress and slows RP progression, highlighting a novel RNAi-based therapeutic strategy for retinal degeneration. Full article

This study aimed to evaluate the effects of fermented blueberry pomace (FBP) supplementation on carcass traits, meat quality, and antioxidant capacity in spent hens and further investigated underlying mechanisms using network pharmacology and molecular docking analyses. A total of 320 Yukou Jingfen No. 8 spent hens (345 days old) were fed a basal diet supplemented with 0, 0.25, 0.5, or 1.0% FBP for 56 days. Each group contained eight replicates with ten hens per replicate. Results showed that 0.25% FBP reduced the percentage of thigh muscle, whereas 0.5% FBP reduced drip loss at 24 h post-mortem in the breast muscle compared to the control group (p < 0.05). Additionally, 0.5% FBP enhanced the total antioxidant capacity compared to the 0.25% group and increased superoxide dismutase activity compared to the control and 0.25% FBP groups (p < 0.05). In the breast muscle, 0.25 and 0.5% FBP reduced drip loss compared to the control group at 48 h post-mortem, while 0.25% FBP upregulated glutathione peroxidase 1 expression more than the other groups (p < 0.05). Network pharmacology analysis identified 302 targets related to the potential bioactive compounds in FBP and 401 targets associated with meat quality, such as core targets of insulin, protein kinase cAMP-activated catalytic subunit beta, steroid receptor coactivator, etc. The identified key signaling pathways included JAK-STAT and PI3K-Akt signaling pathways, which were related to protein synthesis and muscle growth. Molecular docking analysis confirmed strong binding activity between bioactive compounds of FBP and meat quality. In conclusion, dietary FBP supplementation enhances the breast muscle quality of spent hens through the potential bioactive compounds targeting insulin and modulating JAK-STAT and PI3K-Akt signaling pathways, without affecting carcass traits. Moreover, 0.5% FBP exhibited better effects than other treatment groups in spent hens. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that poses an increasing burden on society. It is characterized by the presence of neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques. AD is a multifactorial disease, with one of the strongest genetic risk factors being the APOE4 allele. In this study, we investigated the impact of APOE4 on NF-κB signaling in induced pluripotent stem (iPS) cells. Our results indicate that APOE4 may influence the subcellular localization of the pluripotency marker OCT4, showing a predominantly nuclear localization in APOE4 cells, whereas it appears cytoplasmic in APOE3 cells. Additionally, NF-κB activation via its canonical subunits is blunted in APOE4 cells. Interestingly, APOE4 cells still exhibit increased transcription of key hyperinflammatory markers CCL2, CXCL10 and COX2, which are known NF-κB target genes, and exhibit a significantly higher rate of apoptosis compared to APOE3 cells—independent of TNF-α stimulation. Moreover, an elevated incidence of DNA double-strand breaks was observed in APOE4 cells. However, the precise molecular mechanisms by which APOE4 suppresses NF-κB activation while simultaneously promoting inflammation and apoptosis remain unclear. Further research is required to elucidate these underlying pathways. Full article

Proteasome subunit beta type-9 (PSMB9), a member of the proteasome beta subunit family, encodes the pivotal β1i component of the immunoproteasome. PSMB9 plays a crucial role in antigen processing and presentation; however, its comprehensive role in orchestrating a tumor-immune landscape and regulating the anti-tumor immune responses remains unexplored. Here we investigated the context-dependent functions of PSMB9 by integrating multi-omics data from The Cancer Genome Atlas, Genotype-Tissue Expression database, Human Protein Atlas, Tumor Immunotherapy Gene Expression Resource, and multiple other databases. Moreover, we explored the predictive value of PSMB9 in multiple immunotherapy cohorts and investigated its functional relevance in CAR-T therapy using genome-scale CRISPR/Cas9 screening, gene knockout cell line in vitro, and clinical cohort validation. We found widespread dysregulation in PSMB9 across cancers, predominantly upregulated in most malignancies and associated with advanced pathological stages in specific contexts. PSMB9 was also broadly and negatively correlated with tumor stemness indices. Crucially, PSMB9 expression was robustly linked to anti-tumor immunity by being significantly correlated with immune-pathway activation (e.g., IFN response, cytokine signaling), immune regulatory and immune checkpoint gene expression, and enhanced infiltration of T cells across nearly all tumor types. Consequently, elevated PSMB9 predicted superior response to immune checkpoint inhibitors in multiple cohorts, showing comparable predictive power to established predictive signatures. Furthermore, CRISPR/Cas9 screening identified PSMB9 loss as a novel mechanism of resistance to CD19 CAR T cell therapy, with PSMB9-deficient tumor cells exhibiting a survival advantage under CAR-T pressure, supported by trends in clinical CAR-T outcomes. Our study uncovers PSMB9 as a previously unrecognized critical regulator of the tumor immune landscape in a pan-cancer scope, whose expression orchestrates key immune processes within the tumor microenvironment and serves as a potent biomarker for patient prognosis. Critically, we first established PSMB9 as a novel prognostic indicator for both checkpoint blockade and CAR-T cell therapies, highlighting its dual role as a crucial immune modulator and a promising biomarker for guiding T cell-based immunotherapy strategies across diverse human cancers. Full article