Secreted phosphoprotein 1 (SPP1), also known as osteopontin, is a phosphorylated protein. High SPP1 expression levels have been detected in multiple cancers and are associated with poor prognosis and reduced survival rates. However, only a few pan-cancer analyses have targeted SPP1. We conducted a comprehensive analysis using multiple public databases, including TIMER and TCGA, to investigate the expression levels of SPP1 in 33 different tumor types. In addition, we verified the effect of SPP1 on osteosarcoma. To assess the impact of SPP1 on patient outcomes, we employed univariate Cox regression and Kaplan-Meier survival analyses to analyze overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in these tumor patients. We also explored SPP1 gene alterations in various tumor tissues using cBioPortal. We then examined the relationship between SPP1 and clinical characteristics, TME, immune regulatory genes, immune checkpoints, TMB, and MSI using R language. In addition, we used GSEA to investigate the molecular mechanisms underlying the role of SPP1. Bioinformatics analysis indicated that SPP1 was upregulated in 17 tumors. Overexpression of SPP1 results in poor OS, DSS, and PFI in CESC, ESCA, GBM, LGG, LIHC, PAAD, PRAD, and skin cutaneous melanoma. SPP1 expression was positively associated with immunocyte infiltration, immune regulatory genes, immune checkpoints, TMB, MSI, and drug sensitivity in certain cancers. We found that high expression of SPP1 in osteosarcoma was related to drug resistance and metastasis and further demonstrated that SPP1 can stimulate osteosarcoma cell proliferation via CCND1 by activating the PI3K/Akt pathway. These findings strongly suggest that SPP1 is a potential prognostic marker and novel target for cancer immunotherapy.

BACKGROUND: The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan-cancers.
METHODS: Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross-validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model.
RESULTS: A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36-62.65 months). In the training cohort of 1425 patients, through Lasso regression cross-validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C-indexes of the model for predicting 1-, 3-, 5-, and 10-year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723-8.397; log-rank p < 0.001; validation cohort: HR, 8.429; 95% CI, 6.180-11.497; log-rank p < 0.001).
CONCLUSIONS: The prognostic model based on the nutritional indexes of pan-cancer can divide patients into different survival risk groups and performed well in the validation cohort.

RFC4 is required for DNA polymerase δ and DNA polymerase ε to initiate DNA template expansion. Downregulated RFC4 inhibits tumour proliferation by causing S-phase arrest and inhibiting mitosis, resulting in the reduction of tumour cells. RFC4 has been implicated that it plays an important role in the initiation and progression of cancers, but a comprehensive analysis of the role of RFC4 in cancer has not been performed. We comprehensively analysed the expression, prognosis, methylation level, splicing level, relationship of RFC4 and immune infiltration, and pan-cancer immunotherapy response used various databases (including TCGA, GTEx, UALCAN, Oncosplicing, TIDE, TISCH, HPA and CAMOIP), and experimented its biological function in HCC. Through pan-cancer analysis, we found that RFC4 is significantly upregulated in most tumours. The tumour patients with high expression of RFC4 have poor prognosis. The methylation level and variable splicing level of RFC4 were abnormal in most tumours compared with the adjacent tissues. Furthermore, RFC4 was closely associated with immune cell infiltration in various cancers. RFC4 was significantly co-expressed with immune checkpoints and other immune-related genes. The expression of RFC4 could indicate the immunotherapy efficacy of some tumours. The RFC4 expression was associated with sensitivity to specific small molecule drugs. Cell experiments have shown that downregulated RFC4 can inhibit cell cycle and tumour cell proliferation. We conducted a systematic pan-cancer analysis of RFC4, and the results showed that RFC4 can serve as a biomarker for cancer diagnosis and prognosis. These findings open new perspectives for precision medicine.

Intercellular adhesion molecule 1 (ICAM1) is a cell surface adhesion glycoprotein in the immunoglobulin supergene family. It is associated with several epithelial tumorigenesis processes, as well as with inflammation. However, the function of ICAM1 in the prognosis of tumor immunity is still unclear. This study aimed to examine the immune function of ICAM1 in 33 tumor types and to investigate the prognostic value of tumors. Using datasets from the Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx), Cancer Cell Lines Encyclopedia (CCLE), Human Protein Atlas (HPA), and cBioPortal, we investigated the role of ICAM1 in tumors. We explored the potential correlation between ICAM1 expression and tumor prognosis, gene mutations, microsatellite instability, and tumor immune cell levels in various cancers. We observed that ICAM1 is highly expressed in multiple malignant tumors. Furthermore, ICAM1 is negatively or positively associated with different malignant tumor prognoses. The expression levels of ICAM1 were correlated with the tumor mutation burden (TMB) in 11 tumors and with MSI in eight tumors. ICAM1 is a gene associated with immune infiltrating cells, such as M1 macrophages and CD8+ T cells in gastric and colon cancer. Meanwhile, the expression of ICAM1 is associated with several immune-related functions and immune-regulation-related signaling pathways, such as the chemokine signaling pathway. Our study shows that ICAM1 can be used as a prognostic biomarker in many cancer types because of its function in tumorigenesis and malignant tumor immunity.

There is a close relationship between immune-mediated inflammation and cancer, and there is still controversy over whether rheumatoid arthritis (RA) increases the risk of malignancy. We first used Mendelian randomization (MR) analysis to explore the potential causal relationship between RA and pan-cancer. And verify the effect of immune-mediated inflammation on cancer through intermediate MR analysis. Then we extracted the standardized incidence rate of malignancy in RA patients relative to the general population through large-scale meta-analysis. Finally, we performed pan-cancer analysis on the RA related genes obtained from MR analysis. And perform immune related analysis on key genes to reveal the association between RA and malignancy. The MR analysis demonstrated a negative correlation between RA and pan-cancer (p = 0.008). Autoimmune traits were the main mediating variable for the causal relationship between RA and pan-cancer. Based on the results of the meta-analysis, we validated that RA reduces the risk of developing colorectal cancer (SIR = 0.69, 95% CI 0.53-0.85). Pan-cancer analysis also showed that high expression of RA related genes was negatively correlated with colon adenocarcinoma. IL6R was the gene with the highest correlation among them, and its correlation with immune cells was higher in colorectal cancer than in other malignancy. Our MR study provides evidence that RA was associated with reduced risk of colorectal cancer. This effect is caused by immune-mediated inflammation, with IL6R being a key regulatory gene.

In recent years, C2ORF40 has been identified as a tumor suppressor gene with multiple functions, including roles in cell proliferation, migration, and senescence. To explore the role of the C2ORF40 gene in different tumors, we used multiple databases for analysis. Compared to adjacent normal tissues, C2ORF40 is downregulated in a variety of malignant tumors, including tumors such as breast cancer, colorectal cancer, bladder cancer, hepatocellular carcinoma and prostate cancer. Notably, low expression of the gene is significantly associated with poor overall survival and relapse-free survival rates. In specific cancers including colon cancer and prostate cancer, the expression of C2ORF40 is correlated with the infiltration of CAFs. C2ORF40 is also involved in biological processes such as cell apoptosis and regulation of protein stability. In conclusion, C2ORF40 can hold promise as a prognostic marker for pan-cancer analysis.

BACKGROUND: Mitochondrial outer membrane permeabilisation (MOMP) plays a pivotal role in cellular death and immune activation. A deeper understanding of the impact of tumour MOMP on immunity will aid in guiding more effective immunotherapeutic strategies.
METHODS: A comprehensive pan-cancer dataset comprising 30 cancer-type transcriptomic cohorts, 20 immunotherapy transcriptomic cohorts and three immunotherapy scRNA-seq datasets was collected and analysed to determine the influence of tumour MOMP activity on clinical prognosis, immune infiltration and immunotherapy effectiveness. Leveraging 65 scRNA-Seq datasets, the MOMP signature (MOMP.Sig) was developed to accurately reflect tumour MOMP activity. The clinical predictive value of MOMP.Sig was explored through machine learning models. Integration of the MOMP.Sig model and a pan-cancer immunotherapy CRISPR screen further investigated potential targets to overcome immunotherapy resistance, which subsequently underwent clinical validation.
RESULTS: Our research revealed that elevated MOMP activity reduces mortality risk in cancer patients, drives the formation of an anti-tumour immune environment and enhances the response to immunotherapy. This finding emphasises the potential clinical application value of MOMP activity in immunotherapy. MOMP.Sig, offering a more precise indicator of tumour cell MOMP activity, demonstrated outstanding predictive efficacy in machine-learning models. Moreover, with the assistance of the MOMP.Sig model, FOXO1 was identified as a core modulator that promotes immune resistance. Finally, these findings were successfully validated in clinical immunotherapy cohorts of skin cutaneous melanoma and triple-negative breast cancer patients.
CONCLUSIONS: This study enhances our understanding of MOMP activity in immune modulation, providing valuable insights for more effective immunotherapeutic strategies across diverse tumours.

Aurora kinase B (AURKB), an essential regulator in the process of mitosis, has been revealed through various studies to have a significant role in cancer development and progression. However, the specific mechanisms remain poorly understood. This study, therefore, seeks to elucidate the multifaceted role of AURKB in diverse cancer types. This study utilized bioinformatics techniques to examine the transcript, protein, promoter methylation and mutation levels of AURKB. The study further analysed associations between AURKB and factors such as prognosis, pathological stage, biological function, immune infiltration, tumour mutational burden (TMB) and microsatellite instability (MSI). In addition, immunohistochemical staining data of 50 cases of renal clear cell carcinoma and its adjacent normal tissues were collected to verify the difference in protein expression of AURKB in the two tissues. The results show that AURKB is highly expressed in most cancers, and the protein level of AURKB and the methylation level of its promoter vary among cancer types. Survival analysis showed that AURKB was associated with overall survival in 12 cancer types and progression-free survival in 11 cancer types. Elevated levels of AURKB were detected in the advanced stages of 10 different cancers. AURKB has a potential impact on cancer progression through its effects on cell cycle regulation as well as inflammatory and immune-related pathways. We observed a strong association between AURKB and immune cell infiltration, immunomodulatory factors, TMB and MSI. Importantly, we confirmed that the AURKB protein is highly expressed in kidney renal clear cell carcinoma (KIRC). Our study reveals that AURKB may be a potential biomarker for pan-cancer and KIRC.

BACKGROUND: Several studies have reported a significant relationship between Ephrin receptor A2 (EphA2) and malignant progression in numerous cancers. However, there is a lack of comprehensive pan-cancer analysis on the prognostic value, mutation status, methylation landscape, and potential immunological function of EphA2.
METHODS: Using The Cancer Genome Atlas, Genotype Tissue Expression Database and GEO data, we analysed the differences in EphA2 expression between normal and tumour tissues and the effects of EphA2 on the prognosis of different tumours. Furthermore, using GSCALite, cBioPortal, TISDB, ULCLAN and TIMER 2.0 databases or platforms, we comprehensively analysed the potential oncogenic mechanisms or manifestations of EphA2 in 33 different tumour types, including tumour mutation status, DNA methylation status and immune cell infiltration. The correlation of EphA2 with immune checkpoints, tumour mutational burden, DNA microsatellite instability and DNA repair genes was also calculated. Finally, the effects of EphA2 inhibitors on the proliferation of human glioma and lung cancer cells were verified in cellular experiments.
RESULTS: EphA2 is differentially expressed in different tumours, and patients with overexpression have poorer overall survival. In addition, gene mutations, gene copy number variation and DNA/RNA methylation of EphA2 have been identified in various tumours. Moreover, EphA2 is positively associated with immune infiltration involving macrophages and CD8+ T cells. Further, EphA2 mRNA expression is significantly associated with immune checkpoint in various cancers, especially programmed death-ligand 1. Finally, the EphA2 inhibitor ALW-II-41-27 shows potent anti-tumour activity.
CONCLUSIONS: Our first pan-cancer study of EphA2 provides insight into the prognostic and immunological roles of EphA2 in different tumours, suggesting that EphA2 might be a potential biomarker for poor prognosis and immune infiltration in cancer.

Imbalance in copper homeostasis can be lethal. A recent study found that excess copper induces cell death in a way that has never been characterized before, which is dependent on mitochondrial stress and is referred to as \"cuproptosis.\" The role of cuproptosis in tumors has not yet been elucidated. In this study, we revealed the complex and important roles of cuproptosis regulators and cuproptosis activity in tumors via a comprehensive analysis of multiomics data from more than 10,000 samples of 33 tumor types. We found that the cyclin-dependent kinase inhibitor 2A is the most frequently altered cuproptosis regulator, and the cuproptosis regulator expression is dysregulated in various tumors. Additionally, we developed a cuproptosis activity score to reflect the overall cuproptosis level. On the basis of the expression levels of cuproptosis regulators, tumors can be divided into two clusters with different cuproptosis activities and survival outcomes. Importantly, cuproptosis activity was found to be associated with the prognosis of multiple tumors and multiple tumor-related pathways, including fatty acid metabolism and remodeling of the tumor microenvironment. Furthermore, cuproptosis increased the sensitivity to multiple drugs and exhibited potential to predict the outcome of immunotherapy. We also comprehensively identified cuproptosis-related microRNAs, long noncoding RNAs, and transcription factors. We provided the code corresponding to the results of this study in GitHub (https://github.com/Changwuuu/Cuproptosis-pancancer.git) for reference. In summary, this study reveals important molecular and clinical characteristics of cuproptosis regulators and cuproptosis activity in tumors, and suggests the use of cuproptosis as a promising tumor therapeutic approach. This study provides an important reference point for future cuproptosis-related research.