Lactate, a characteristic metabolite of the tumor microenvironment (TME), drives immunosuppression and promotes tumor progression. Material-engineered strategies for intratumoral lactate modulations demonstrate their promise for tumor immunotherapy. However, understanding of the inherent interconnections of material-enabled lactate regulation, metabolism, and immunity in the TME is scarce. To address this issue, urchin-like catalysts of the encapsulated Gd-doped CeO 2 , syrosingopine, and lactate oxidase are used in ZIF-8 (USL, where U, S, and L represent the urchin-like Gd-doped CeO 2 @ZIF-8, syrosingopine, and lactate oxidase, respectively) and orthotopic tumor models. The instructive relationships of intratumoral lactate depletion, metabolic reprogramming, and immune activation for catalytic immunotherapy of tumors is illustrated. The catalysts efficiently oxidize intratumoral lactate and significantly promote tumor cell apoptosis by in situ-generated •OH, thereby reducing glucose supply and inducing mitochondrial damage via lactate depletion, thus reprogramming glycometabolism. Subsequently, such catalytic metabolic reprogramming evokes both local and systemic antitumor immunity by activating M1-polarizaed macrophages and CD8 + T cells, leading to potent antitumor immunity. This study provides valuable mechanistic insights into material-interfered tumor therapy through intratumoral lactate depletion and consequential connection with metabolic reprogramming and immunity remodeling, which is thought to enhance the efficacy of immunotherapy.
Background: Cuproptosis or copper-dependent cell death is a newly identified non-apoptotic cell death pathway which plays a critical role in the development of multiple cancers. Long non-coding RNAs (lncRNAs) are increasingly recognized as crucial regulators of programmed cell death and lung adenocarcinoma (LUAD) development, and a comprehensive understanding of cuproptosis-related lncRNAs may improve prognosis prediction of LUAD. However, few studies have explored the association of cuproptosis-related lncRNAs with the prognosis of LUAD. Methods:The RNA sequencing data and corresponding clinical information of patients were extracted from The Cancer Genome Atlas (TCGA) database. Five hundred LUAD patients were randomly divided into a training (n=250) and a testing cohort (n=250). Pearson correlations were performed to identify cuproptosis-related lncRNAs, and univariate Cox regression was performed to screen prognostic lncRNAs.A cuproptosis-related lncRNAs prognostic signature (CLPS) was constructed by the least absolute shrinkage and selection operator Cox regression. Kaplan-Meier analysis, receiver operating characteristic curves, and multivariate Cox regression were performed to verify the prognostic performance of CLPS. Additionally, immune cell infiltration was estimated using the single-sample gene-set enrichment analysis. pRRophetic algorithm and Tumor Immune Dysfunction and Exclusion algorithm were used to assess the immunotherapy and chemotherapy response, respectively.Results: CLPS was established based on 61 cuproptosis-related prognostic lncRNAs and exhibited a satisfactory performance predicting LUAD patients' survival (area under the curve at 1, 3, 5 years was 0.784, 0.749, 0.775, respectively). multivariate Cox analysis confirmed the independent prognostic effect of CLPS (hazard ratio: 1.128; 95% confidence interval: 1.071-1.189; P<0.001), and a nomogram containing it exhibited robust validity in prognostic prediction. We further demonstrated a higher CLPS-risk score was associated with lower levels of signatures including immune cell infiltration, immune activation, and immune checkpoints. Conclusions:The CLPS serves as an effective predictor for the prognosis and therapeutic responses of LUAD patients. Our findings provide promising novel biomarkers and therapeutic targets for LUAD.
Background: Alternative splicing (AS) is a critical mechanism of post-transcriptional regulation and has been widely reported to be associated with the tumor progression and tumor microenvironment (TME) formation. However, the role of AS in lung adenocarcinoma (LUAD) has not been clearly elucidated. This study presents a comprehensive analysis exploring the impact of AS on prognosis and TME in LUAD. Methods:The gene expression transcriptome profiles and survival data were obtained from The Cancer Genome Atlas (TCGA) database, and the splicing profiles were obtained from the TCGA SpliceSeq database.Base on prognostic AS events, a prognostic signature was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) regression followed by multivariate Cox regression analysis. Survival outcomes was analyzed using the Kaplan-Meier method and the predictive performance of the signature was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, the landscape of the TME was assessed by ESTIMATE, Microenvironment Cell Population (MCP)-counter, and single-sample Gene-Set Enrichment Analysis (ssGSEA) algorithms.Results: A total of 127 prognostic AS events with P value <0.001 from 89 genes in LUAD were confirmed.A prognostic signature was constructed based on 20 prognostic AS events. Kaplan-Meier survival analysis demonstrated that higher risk scores were associated with poorer overall survival (OS). The area under the ROC curve of risk scores predicting the 1-, 3-, and 5-year survival probability were 0.791, 0.847, and 0.832, respectively. Furthermore, significant relationship was observed between the prognostic signature and the landscape of the TME. High-risk patients had lower stromal/immune scores, higher tumor purity, and significantly decreased abundance of majority immune cells, and immune-related signatures (P<0.05). Finally, a potential regulatory mechanism of the AS events is displayed in a regulatory network.Conclusions: This research highlights the prognostic value of AS events for patients with LUAD and provide new insight into the regulation of the TME by AS. Notably, AS may affect the patient's prognosis by altering the TME. Our findings provide important guidance for the development of novel biomarkers and therapeutic targets in patients with LUAD.
Background: The non-negligible role of epigenetic modifications in cancer development and tumor microenvironment (TME) has been demonstrated in recent studies. Nonetheless, the potential regulatory role of N7-methylguanosine (m7G) modification in shaping and impacting the TME remains unclear.Methods: A comprehensive analysis was performed to explore the m7G modification patterns based on 24 potential m7G regulators in 817 lung adenocarcinoma (LUAD) patients, and the TME landscape in distinct m7G modification patterns were evaluated. The m7G score was established based on principal component analysis (PCA) to quantify m7G modification patterns and evaluate the TME cell infiltrating characteristics of individual tumors. Further, correlation analyses of m7Gscore with response to chemotherapy and immunotherapy were performed.Results: We identified three distinct m7G modification patterns with the biological pathway enrichment and TME cell infiltrating characteristics corresponded to immune-desert, immune-inflamed and immune-excluded phenotype, respectively. We further demonstrated the m7Gscore could predict the TME infiltrating characteristics, tumor mutation burden (TMB), response to immunotherapy and chemotherapy, as well as prognosis of individual tumors. High m7Gscore was associated with increased component of immune cell infiltration, low TMB and survival advantage, while low m7Gscore was linked to decreased immune cell infiltration and increased TMB. Additionally, patients with lower m7Gscore demonstrated significant therapeutic advantages.Conclusion: This study demonstrated the regulatory mechanisms of m7G modification on TME formation and regulation of lung adenocarcinoma. Identification of individual tumor m7G modification patterns will contribute to the understanding of TME characterization and guiding more effective immunotherapy strategies.
Background: Liver transplantation (LT) is the optimal treatment option for hepatocellular carcinoma (HCC) meeting the Extended Liver Transplant Criteria (ELTC), but it is only offered for the minority. The optimal alternative strategy for HCCs beyond the Milan criteria (BMC) but meeting the ELTC, which is defined as modestly beyond the Milan criteria (MBMC) here, is a matter of concern. The aim of this study was to evaluate the survival benefits of LR compared with transarterial chemoembolization (TACE) for MBMC-HCCs. Methods: From January 2010 to October 2021, from fifteen Chinese hepatobiliary centres, 1110 MBMC-HCC patients with Child‒Pugh A who underwent LR (n = 424) or TACE (n = 686) were included. Overall survival (OS) benefit of LR versus TACE in the MBMC-HCC cohort was compared based on a propensity score matching (PSM) and was further validated in addition BMC-HCC cohorts selected according to other extended LT criteria (Asan criteria, up-to-7 criteria, French alpha-foetoprotein model and Metroticket 2.0 model). Results: Survival analyses in the MBMC-HCC cohort as well as other 4 BMC-HCC cohorts demonstrated that OS was significantly longer in the LR group than that in the TACE group (all log-rank P < 0.001). After a 1:1 PSM in the MBMC-HCC cohort, multivariate analysis and subsequent subgroup analyses based on tumour burden and other important covariates further confirmed the robust survival advantage of LR compared to TACE. Conclusions: LR rather than TACE is highly recommended as the preferred alternative for potential LT candidates with MBMC-HCC regardless of tumor burden.
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