BackgroundCuproptosis is a copper-dependent cell death mechanism that is associated with tumor progression, prognosis, and immune response. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of triple-negative breast cancer (TNBC) remains unclear.Patients and methodsIn total, 346 TNBC samples were collected from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets, and were classified using R software packages. The relationships between the different subgroups and clinical pathological characteristics, immune infiltration characteristics, and mutation status of the TME were examined. Finally, a nomogram and calibration curve were constructed to predict patient survival probability to improve the clinical applicability of the CRG_score.ResultsWe identified two CRG clusters with immune cell infiltration characteristics highly consistent with those of the immune-inflamed and immune-desert clusters. Furthermore, we demonstrated that the gene signature can be used to evaluate tumor immune cell infiltration, clinical features, and prognostic status. Low CRG_scores were characterized by high tumor mutation burden and immune activation, good survival probability, and more immunoreactivity to CTLA4, while high CRG_scores were characterized by the activation of stromal pathways and immunosuppression.ConclusionThis study revealed the potential effects of CRGs on the TME, clinicopathological features, and prognosis of TNBC. The CRGs were closely associated with the tumor immunity of TNBC and are a potential tool for predicting patient prognosis. Our data provide new directions for the development of novel drugs in the future.

Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro . Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.

Accumulating evidences demonstrated that microglia activation and the autocrine loop of tumor necrosis factor-α (TNFα) greatly contribute to the pathogenesis of several CNS diseases. TNFα exerts its biological effects by interacting with two different receptors: TNF receptor 1 (TNFR1) and TNFR2. The classic proinflammatory activity of TNFα is mainly mediated by TNFR1. In the present study, we found that TNFR1 was modificated by N-glycosylation on Asn151 and Asn202 in microglia. The N-glycosylation of TNFR1 could facilitate its capability of binding to TNFα and further promote the formation of TNFα autocrine loop in microglia stimulated by TNFα, resulting in excessive microglia activation and CNS inflammation. All these processes were related to TNFR1-mediated NF-κB pathways. Elimination of N-glycosylation did not affect the subcellular transportation and cell surface localization of TNFR1, but suppressed ligand-binding affinity. These findings indicated that the N-glycosylation of TNFR1 played an important role during microglia activation in CNS inflammation. By this study, we aimed to provide some valuable experimental evidence for a better understanding of the significance of protein glycosylation in microglia inflammatory activation and CNS disease.