INTRODUCTION:Knowledge of the mechanisms through which common single-nucleotide polymorphisms (SNPs) modulate colorectal cancer (CRC) susceptibility is central to elucidating the molecular basis of this disease. Genome-wide association studies (GWAS) reveal noncoding SNPs influencing CRC susceptibility, yet their functional mechanisms, particularly through gene expression dysregulation, DNA methylation alterations, and interactions with gut microbiota, remain uncharacterized. Through integrative analysis, systematically exploring the effects of genetic variations on gene expression heterogeneity, DNA methylation, and gut microbiome is expected to yield potential biomarkers for early diagnosis and intervention of CRC. METHODS:An integrative framework is developed to prioritize causal risk genes at CRC-associated GWAS loci, applying the SMR&HEIDI (Summary-data-based Mendelian randomization and heterogeneity in dependent instruments) and TSMR (Two-sample Mendelian Randomisation) methods. The findings were validated via gene expression and TF binding affinity. RESULTS:10 tissue-specific gene-SNP pairs, 3 blood eQTL-gene pairs, 26 gene-CpG-SNP regulatory modules, and 39 microbiota-associated gene-SNP pairs are identified. A few potential regulatory influences on CRC development associated with genes and variants, such as POU5F1B and rs10797801, were identified. Moreover, the genetic variants disrupted TF binding affinity while only a few promoted the binding of transcription factors (TFs). DISCUSSION:The data integration enabled us to prioritize genes according to different regulatory mechanisms, such as gene expression and DNA methylation, and bridge the gap between statistical associations and biological functionality. CONCLUSION:Multi-omics integration reveals some causal risk genes and variants implicated in CRC. These findings offer novel insight into the molecular mechanisms underlying CRC susceptibility and provide valuable clues for diagnosis and therapeutic intervention strategies.

Neuroendocrine bladder carcinoma (NEBC) is an aggressive and therapy-resistant cancer with poor prognosis. Although lineage plasticity drives urothelial-to-neuroendocrine transdifferentiation, intermediate states remain poorly characterized. Through transcriptomic profiling of public datasets, we define a lineage plasticity-associated signature in bladder cancer. We analyze 64,756 in-house and 201,720 public single-cell transcriptomes from NEBC and urothelial carcinoma (UC), identifying TPX2high bladder cancer cell subpopulation with increased lineage plasticity, supported by multi-cohort histological validation. TPX2high cells lack canonical neuroendocrine markers and are associated with adverse clinical outcomes. TPX2high cells exhibit dysregulated cell cycle progression and occupy a suppressive niche associated with CD8+ T cell exhaustion. In vitro and in vivo, TPX2 promotes lineage plasticity and induces T cell exhaustion. In preclinical patient-derived organoids (PDOs) and patient-derived xenograft (PDX) models, CDK4/6 inhibition plus immune checkpoint blockade demonstrates potent antitumor efficacy. Overall, our findings suggest this combination therapy as a promising therapeutic strategy for TPX2high and NEBC patients.

Copy number variations (CNVs) in several genetic regions are associated with cancer susceptibility and poor clinical outcomes. Currently, the role of CNVs in Non-Small Cell Lung Cancer (NSCLC) is relatively vague. This study investigates the CNVs profile in early-stage NSCLC. We retrospectively analyzed the next-generation sequencing (NGS) data of tumor tissue specimens from NSCLC patients over the past 3 years in our center. All samples were obtained by surgical resection, and clinical characteristics were collected for further analysis. A total of 102 early-stage NSCLC performed NGS in our study, the mean age was 60.5 years, with 51% female. Genomic analysis revealed that 85.3% (87/102) patients had driver gene mutations, predominantly EGFR mutations (72/102) and ALK fusions (6/102). CNVs were observed in 29 NSCLC patients, including 22 with EGFR mutations, 1 with ALK fusion, 1 with BRAF V600E, and 5 without driver gene mutations. Among patients with CNVs, 9p21 (CDKN2A/CDKN2B) copy number losses were most frequent (24.1%, 7/29), followed by EGFR copy number gains (20.7%, 6/29), MYC copy number gains (13.8%, 4/29), and GATA1 copy number losses (13.8%, 4/29). There was no significant difference in age (median: 63 vs 61 years, P=0.504, Mann-Whitney U test) and sex (male: 66% vs 34%, P=0.221, chi-square test) between patients with and without CNVs. A significant trend of increased CNVs was observed in smokers compared to non-smokers (CNVs: 45.5% vs. 23.8%, P=0.046, chi-square test). Patients with small tumors accompanied by lymph node metastasis showed a significantly higher incidence of driver gene fusions than those without lymph node metastasis (T1-2N1-2 vs. T1-2N0 = 50.0% vs. 7.7%, P<0.001, chi-square test). However, no significant difference in CNVs incidence was found between these groups. The prognostic value of CNVs requires further validation through follow-up. Our study reveals a high prevalence of copy number losses of 9p21 (CDKN2A/CDKN2B) exists in early-stage non-small cell lung cancer. And we find that NSCLC patients with a history of smoking are more likely to have copy number variations. Jun Wang, Ning Gao, Ding Zhang. Real-world data of resected early-stage non-small cell lung cancer (NSCLC) harboring copy number variations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4665.

Adoptive cell therapy (ACT), an important component of tumor immunotherapy, achieves precise anti-cancer effects by reinfusing in vitro-processed immune cells, providing a new option for advanced tumor patients with resistance to chemotherapy or targeted therapy. Among them, antigen-specific cytotoxic T lymphocyte (ACTL) therapy innovatively integrates the natural expansion advantage of tumor-infiltrating lymphocytes (TILs) and the precise antigen-presenting mechanism of recombinant adeno-associated virus-transfected dendritic cells (rAAV-DCs), becoming a research focus. This case report describes a patient with IVa stage advanced lung adenocarcinoma with multiple intrapulmonary metastases carrying an epidermal growth factor receptor (EGFR) exon 19 deletion mutation. After receiving treatment with the third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) drug osimertinib, the patient developed acquired resistance with unknown mechanisms and was in an immune-suppressed state. Subsequently, the patient received ACTL therapy and ultimately achieved a clinical complete response (cCR) and maintained it for six years of follow-up. This case is the first to report that ACTL therapy has achieved “clinical cure” in a patient with acquired EGFR-TKI resistance, indirectly suggesting the underlying mechanism of this therapy in reshaping the tumor immune microenvironment (TME). It illustrates that ACTL, as a novel cellular immunotherapy with both target precision and immune balance, has demonstrated potential in overcoming targeted resistance in advanced lung cancer and inducing deep remission.

Bladder cancer (BCa) remains one of the most prevalent malignancies worldwide, with cisplatin-based combination chemotherapy as the cornerstone of adjuvant treatment. However, cisplatin resistance frequently arises in advanced BCa, limiting therapeutic efficacy. Comparative proteomic analysis of cisplatin-sensitive and -resistant BCa cells identified phosphodiesterase 10A (PDE10A) as significantly downregulated at the protein level in resistant cells, despite unchanged mRNA levels, indicating post-transcriptional regulation. Functional assays demonstrated that PDE10A enhanced cisplatin sensitivity by promoting apoptosis. Mechanistically, the E3 ubiquitin ligase RNF220 directly interacted with PDE10A, facilitating its ubiquitination and degradation under cisplatin-resistant conditions. RNF220 overexpression markedly reinforced cisplatin resistance in vitro and in vivo. Furthermore, N6-methyladenosine (m6A) modification mediated by METTL3 stabilized RNF220 mRNA in an IGF2BP2-dependent manner. Additionally, RNF220 promoted PD-L1 expression by destabilizing PDE10A, thereby facilitating immune evasion in BCa. These findings establish RNF220 as a pivotal ubiquitinase that drives both cisplatin resistance and immune escape through PDE10A destabilization, highlighting its potential as a therapeutic target to enhance chemotherapy and immunotherapy efficacy in advanced BCa.

Objective: To present a modified technique for robot-assisted laparoendoscopic single-site retroperitoneal nephroureterectomy (RLESS-RNU) with bladder cuff excision and evaluate its effectiveness as a minimally invasive approach for managing upper tract urothelial carcinoma (UTUC). Methods: Fifteen patients who underwent RLESS-RNU for UTUC between April 2020 and June 2021 were reviewed at our medical institution (The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China), from our prospectively maintained institutional database. The da Vinci (R) Xi system (Intuitive Surgical, Sunnyvale, CA, USA) was utilized for surgical procedures in all patients. An in-depth analysis was conducted on their baseline demographic characteristics, pathological factors, and perioperative details. The complete surgical process and details are elaborated. Results: The median age of 15 patients was 67 years. The final pathology demonstrated 47% (7/15) patients with pT1 or lower and 47% (7/15) with pT3; one patient could not undergo pathological staging because of preoperative chemotherapy. The perioperative outcomes revealed that the mean operative time was 185 (standard deviation [SD] 23.05) min. The mean times of the trocar placement for primary and second docking were 15.00 (SD 0.85) min and 8.00 (SD 0.52) min, respectively. The median estimated blood loss was 55 mL. The mean drainage tube duration and postoperative hospital stay were 7.50 days and 11.00 days, respectively. After a mean follow-up period of 24.20 months, the relapse-free survival rate was 87%. Two patients experienced disease progression: one patient exhibited multifocal evidence of non-muscle invasive bladder cancer, and the other patient developed systemic recurrence. Conclusion: This study demonstrates that the modified technique for RLESS-RNU is safe and satisfactory for UTUC. (c) 2025 Editorial Office of Asian Journal of Urology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Myocardial dysfunction is a significant complication of sepsis that is associated with elevated mortality rates. Transmembrane BAX inhibitor motif containing 1 (TMBIM1), a stress-responsive protein, has garnered interest in the field of cardiovascular disease for its cardioprotective properties. Nevertheless, the role of TMBIM1 on sepsis-induced cardiac dysfunction (SICD) remains unknown. Here, our findings revealed a significant elevation in TMBIM1 expression within the myocardium following endotoxin challenge and further demonstrate the cardioprotective effects of TMBIM1 through adenovirus-mediated gene manipulation. Notably, lipopolysaccharide exposure markedly induced mitochondrial dysfunction in cardiomyocytes, which was effectively alleviated by TMBIM1 overexpression, while TMBIM1 knockdown exacerbated this dysfunction. Moreover, in cardiomyocytes subjected to endotoxin challenge, TMBIM1 was observed to interact with Parkin, facilitating its translocation from the cytosol to damaged mitochondria. This interaction enhanced the activation of mitophagy, thereby promoting the clearance of dysfunctional mitochondria and subsequently mitigating cellular injury. Hence, targeting TMBIM1 could be a novel therapeutic strategy for treating SICD.

Non–small cell lung cancer (NSCLC) is a widespread and serious global malignancy. This study aimed to examine the clinical relevance of serum exosomal SNORD116 and SNORA21 as novel diagnostic biomarkers for NSCLC. Serum exosomes from 226 healthy controls and 305 NSCLC patients were isolated by ultracentrifugation. Characterization of exosomes was conducted by qNano, transmission electron microscopy (TEM) and Western immunoblotting. RT-PCR revealed snoRNAs that were differentially expressed. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance. In NSCLC patients, the levels of serum exosomal SNORD116 and SNORA21 were significantly reduced compared to those in healthy controls (P < 0.0001 for both). ROC curves showed AUC values of 0.738 and 0.761. By combining SNORD116 and SNORA21 with traditional blood biomarkers CYFRA21–1 and carcinoembryonic antigen (CEA), the AUC increased to 0.917. Moreover, these two exosomal snoRNAs distinguished between patients with metastatic NSCLC (n = 132) and those with non-metastatic NSCLC (n = 173) significantly (P < 0.0001 for both). The ROC curves gave AUC values of 0.743 and 0.694, respectively. The combined analysis raised the AUC to 0.751. The diagnostic power of these two exosomal snoRNAs combined with CYFRA21–1 and CEA increased to 0.784. This study demonstrated that serum exosomal SNORD116 and SNORA21 can be used as potential promising non–invasive diagnostic biomarkers for NSCLC.

Background: The effect of the expression of the newly identified immune checkpoint, T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) on NK cells in core binding factor-acute myeloid leukemia (CBF-AML) remains to be investigated. Methods: Fresh bone marrow samples from a total of 39 newly diagnosed CBF-AML patients and 25 healthy donors (HDs) were collected for testing the phenotype and function state of total NK, CD56bright, and CD56dim NK cell subsets after in vitro stimulation. Results: The frequencies of TIGIT+ cells in total NK, CD56bright, and CD56dim NK cell subsets had no significant difference between patients and HDs. TNF-α and INF-γ levels were uniformly lower in TIGIT+ cells than the corresponding TIGIT− cells in all HDs, whereas those for TIGIT+ to TIGIT− cells in patients were highly heterogenous; TIGIT expression was not related to PFP and GZMB expression in HDs, whereas it was related to higher intracellular PFP and GZMB levels in patients. Patients’ TIGIT+ NK cells displayed lower K562 cell-killing activity than their TIGIT− NK cells. In addition, high frequencies of TIGIT+ cells in total NK and CD56dim NK cells were associated with poor RFS. Conclusions: TIGIT expression affected the diagnostic bone marrow-sited NK cell function and had prognostic significance in CBF-AML patients.

In the evolving field of cancer immunotherapy, EGFR-mutated non-small cell lung cancer (NSCLC) poses a significant obstacle due to its inherent resistance to conventional treatments. The development of an effective strategy to overcome this resistance remains a challenge. Here we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a prime architect in the immune evasion phenotype induced by EGFR mutations. Mechanistically, in the presence of EGFR mutations, the expression of GFPT2, typically low in normal tissues, is significantly upregulated via the EGFR/IRE1α/Xbp1s signaling pathway. This results in a significant increase in intracellular UDP-GlcNAc levels, altering N-glycosylation profiles extensively. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and also amplifies CD73 glycosylation to intensify adenosine-mediated suppression of CD8+T cells. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 also hinders the infiltration of CD8+T cells into tumors by regulating EGFR glycosylation and subsequent secretion of CXCL10 and VEGF. The validation of this GFPT2-mediated immune evasion phenotype is substantiated by compelling clinical evidence. We further identified a GFPT2 isoform-specific inhibitor that can enhance the efficacy of PD-1 blockade therapy beyond current strategies, as evidenced by results in xenograft models and patient-derived organoids. Taken together, our results highlight the potential of GFPT2 as a metabolic checkpoint in controlling immune escape in EGFR-mutated NSCLC, offering an innovative and druggable target to bolster immunotherapy outcomes in NSCLC with EGFR mutations.

Breast cancer is one of the malignant tumors with a high incidence and mortality rate among women worldwide, and its prevalence is increasing year by year, posing a serious health risk to women. UTP23 (UTP23 Small Subunit Processome Component) is a nucleolar protein that is essential for ribosome production. As we all know, disruption of ribosome structure and function results in improper protein function, affecting the body's normal physiological processes and promoting cancer growth. However, little research has shown a connection between UTP23 and cancer. We analyzed the mRNA expression of UTP23 in normal tissue and breast cancer using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, and the protein expression of UTP23 using The Human Protein Atlas (HPA) database. Next, we examined the relationship between UTP23 high expression and Overall Survival (OS) using Kaplan-Meier Plotters and enriched 980 differentially expressed genes in UTP23 high and low expression samples using GO/KEGG and GSEA to identify potential biological functions of UTP23 and signaling pathways that it might influence. Finally, we also investigated the relationship between UTP23 and immune infiltration and examined the effect of UTP23 on the proliferation of human breast cancer cell lines by knocking down UTP23. We found that UTP23 levels in breast cancer patient samples were noticeably greater than those in healthy individuals and that high UTP23 levels were strongly linked with poor prognoses (P = 0.008). Functional enrichment analysis revealed that UTP23 expression was connected to the humoral immune response. Besides, UTP23 expression was found to be positively correlated with immune cell infiltration. Furthermore, UTP23 knockdown has been shown to inhibit the proliferation of human breast cancer cells MDA-MB-231 and HCC-1806. Taken together, our study demonstrated that UTP23 is a promising target in detecting and treating breast cancer and is intimately linked to immune infiltration.

Stachyose (STA) is a prebiotic with poor oral bioavailability. In this study, we developed stachyose caproate (C6STA), as a novel STA derivative, to demonstrate its high adsorption rate via oral administration. Pharmacokinetic analysis reveals that after absorption, the STA derived from C6-STA reaches its highest peak in the blood, liver, and kidney at 20 min, 30 min, and 12-24 h, with approximate levels of 1200 mu g/mL, 0.14 mu g/mL, and 0.2-0.3 mu g/mL, respectively. In addition, the accumulation of STA in prostate tissues of mice with castration-resistant prostate cancer (CRPC) (1.75 mu g/mg) is 10-fold higher than that in normal prostate tissues (0.14 mu g/mg). The analysis also reveals that C6-STA has t 1/2 of 12.8 h and T max of 0.25 h, indicating that it has the potential to be used as a promising drug in clinical practice. The toxicological evaluation shows no obvious side effects of C6STA in mice administered with a 0.2 g/kg intragastric dose. Pharmacodynamic analysis and mechanism investigation of C6-STA show its ability to inhibit peroxiredoxin 5 (PRDX5) enzyme activity, disrupt PRDX5-nuclear factor erythroid 2-related factor 2 (NRF2) interaction, and decrease NAD(P)H P )H quinone dehydrogenase 1 (NQO1) levels. NQO1 decrease further causes the accumulation of quinone radicals, which ultimately leads to the apoptosis of LNCaP cell-derived drug-tolerant persister (DTP) cells and slows CRPC progression. Our study discovered the anti-tumor activity of stachyose and shows that prebiotics have biological functions in vivo besides in the gut. Further investigation of C6-STA, especially in CRPC patients, is warranted.

Introduction:Pheochromocytomas (PCC) and paragangliomas (PGL) (collectively PPGL) are a type of rare hypervascular neuroendocrine tumors that are very challenging to treat. This study aimed to determine the efficacy and safety of the multi-tyrosine kinase inhibitor anlotinib for the treatment of locally advanced or metastatic (LA/M) PPGL.Methods:A total of 37 eligible patients with unresectable or progressive LA/M PPGL were enrolled. Of them, 27 patients received anlotinib alone (n = 19) or in combination (n = 8) with radionuclide therapies, including peptide receptor radionuclide therapy (PRRT) and iodine 131 meta-iodobenzylguanidine (131I-MIBG). The primary endpoints included objective response rate (ORR), defined as partial response (PR) or complete response (CR), and disease-control rate, defined as PR, CR, or stable disease (SD). The secondary endpoints were progression-free survival (PFS), duration of response, and drug safety.Results:In the efficacy evaluation for all 27 patients, the ORR was 44.44% (95% CI: 24.4%-64.5%) and disease-control rate was 96.29% (95% CI: 88.7%-100%). Twelve cases (44.44%) achieved PR, 14 (51.85%) SD. The median PFS was 25.2 months (95% CI: 17.2 months to not reached). PFS was shorter in the anlotinib monotherapy group than in the group receiving anlotinib in combination with radionuclide therapy (P = .2). There were no serious treatment-related AEs.Conclusion:Anlotinib monotherapy or in combination with radionuclide therapies shows promising efficacy and safety for the treatment of LA/M PCC and PGL. Multi-tyrosine kinase inhibitors might represent a novel therapeutic strategy for patients with PPGL; however, large-scale prospective randomized, blinded, controlled clinical research studies are required.

BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is associated with a high prevalence of cancer-related deaths. The survival rates of patients are significantly lower in late-stage ccRCC than in early-stage ccRCC, due to the spread and metastasis of late-stage ccRCC, surgery has not reached the goal of radical cure, and the effect of traditional radiotherapy and chemotherapy is poor. Thus, it is crucial to accurately assess the prognosis and provide personalized treatment at an early stage in ccRCC. This study aims to develop an efficient nomogram model for stratifying and predicting the survival of ccRCC patients based on tumor stage.METHODS:We first analyzed the microarray expression data of ccRCC patients from the Gene Expression Omnibus (GEO) database and categorized them into two groups based on the disease stage (early and late stage). Subsequently, the GEO2R tool was applied to screen out the genes that were highly expressed in all GEO datasets. Finally, the clinicopathological data of the two patient groups were obtained from The Cancer Genome Atlas (TCGA) database, and the differences were compared between groups. Survival analysis was performed to evaluate the prognostic value of candidate genes (PSAT1, PRAME, and KDELR3) in ccRCC patients. Based on the screened gene PSAT1 and clinical parameters that were significantly associated with patient prognosis, we established a new nomogram model, which was further optimized to a single clinical variable-based model. The expression level of PSAT1 in ccRCC tissues was further verified by qRT-PCR, Western blotting, and immunohistochemical analysis.RESULTS:The datasets GSE73731, GSE89563, and GSE150404 identified a total of 22, 89, and 120 over-expressed differentially expressed genes (DEGs), respectively. Among these profiles, there were three genes that appeared in all three datasets based on different stage groups. The overall survival (OS) of late-stage patients was significantly shorter than that of early-stage patients. Among the three candidate genes (PSAT1, PRAME, and KDELR3), PSAT1 was shown to be associated with the OS of patients with late-stage ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, neoadjuvant therapy, and PSAT1 level were significantly associated with patient prognosis. The concordance indices were 0.758 and 0.725 for the 3-year and 5-year OS, respectively. The new model demonstrated superior discrimination and calibration compared with the single clinical variable model. The enhancer PSAT1 used in the new model was shown to be significantly overexpressed in tissues from patients with late-stage ccRCC, as demonstrated by the mRNA level, protein level, and pathological evaluation.CONCLUSION:The new prognostic prediction nomogram model of PSAT1 and clinicopathological variables combined was thus established, which may provide a new direction for individualized treatment for different-stage ccRCC patients.

Transcriptional enhanced associate domain (Tead)-mediated Hippo signaling pathway regulates diverse physiological processes; its dysfunction has been implicated in an increasing number of human gynecological cancers. The transcriptional coactivator with PDZ-binding motif (Taz) binds to and then activates Tead through forming a three-helix bundle (THB) at their complex interface. The THB is defined by a double-helical hairpin from Tead and a single α-helix from Taz, serving as the key interaction hotspot between Tead and Taz. In the present study, the helical hairpin was derived from Tead protein to generate a hairpin segment, which is a 25-mer polypeptide consisting of a longer helical arm-1 and a shorter helical arm-2 as well as a flexible loop linker between them. Dynamics simulation and energetics characterization revealed that the hairpin peptide is intrinsically disordered when splitting from its protein context, thus incurring a large entropy penalty upon binding to Taz α-helix. A disulfide bridge was introduced across the two helical arms of hairpin peptide to obtain a strong binder termed TAZ-hTrap, which can maintain in a considerably structured, native-like conformation in unbound state, and the entropy penalty was minimized by disulfide stapling to effectively improve its affinity toward the α-helix. These computational findings can be further substantiated by circular dichroism and fluorescence polarization at molecular level, and viability assay also observed a potent cytotoxic effect on diverse human gynecological tumors at cellular level. In addition, we further demonstrated that the TAZ-hTrap has a good selectivity for its cognate Taz over other noncognate proteins that share a high conservation with the Taz α-helix.

In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked innate resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC. Mechanistically, under EGFR mutation condition, GFPT2 expression, which is typically low in normal tissues, is highly induced via EGFR/IRE1α/Xbp1s signaling axis, leading to a significant increase in intracellular UDP-GlcNAc and consequently, an altered N-glycosylation profile. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and amplifies CD73 glycosylation, thereby intensifying adenosine-mediated CD8+T cells suppression. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 regulates EGFR glycosylation, which consequentially modulates the EGFR-dependent secretion of CXCL10 and VEGF, thus impeding CD8+T cell infiltration within tumors. We further identified a GFPT2 isoform-specific inhibitor that potentiates PD-1 blockade therapy beyond that of existing strategy, corroborated by results in xenografts and patient-derived organoids. Together, these findings illuminate the promising therapeutic potential of GFPT2 as a metabolic checkpoint, offering an innovative approach to invigorate immunotherapy in NSCLC with EGFR mutations.### Competing Interest StatementThe authors have declared no competing interest.