Background: Immunotherapy has evolved as a critical option to treat diverse cancers. The active response to immunotherapy relies on the unique interaction between cancer and the tumor microenvironment (TME). Angiogenesis is one of the hallmarks of cancer. However, the association between angiogenesis and clinical outcome, immune cell infiltration, and immunotherapy remains unknown in gastric cancer (GC).Methods: We systematically assessed 36 angiogenesis-associated genes (AAGs) and comprehensively identified the correlation between angiogenesis and transcriptional patterns, prognosis, and immune cell infiltration. The AAG_score was applied to quantify the angiogenesis subtypes of each patient. We then evaluated their values in prognostic prediction and therapeutic responses in GC.Results: We discussed the mutations of AAGs in GC specimens from genetic levels and identified their expression patterns from TCGA and GEO cohorts. We determined two different molecular subtypes and observed that AAG mutations were related to patients’ clinicopathological characteristics, prognosis, and infiltrating TME. Next, an AAG_score for predicting overall survival (OS) was established and its reliable predictive ability in GC patients was confirmed. Furthermore, we created a highly reliable nomogram to facilitate the clinical viability of the AAG_score. A low AAG_score, characterized by elevated microsatellite instability-high, mutation burden, and immune activation, demonstrated a superior OS. Additionally, the AAG_score was remarkedly correlated with the cancer stem cell index and drug susceptibility.Conclusion: Collectively, we identified a prognostic AAG signature for GC patients. This signature may contribute to clarifying the characteristics of TME and enable the exploration of more potent immunotherapy strategies.

Background: S100A2, a member of the S100 protein family, is abnormally expressed and plays a vital role in multiple cancers. However, little is known about the clinical significance of S100A2 in endometrial carcinoma. Methods: Clinicopathological data were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). First, the expression and prognostic value of different S100 family members in endometrial carcinoma were evaluated. Subsequently, the Kaplan–Meier plotter and Cox regression analysis were used to assess the prognostic significance of S100A2, while the association between S100A2 expression and clinical characteristics in endometrial carcinoma was also analyzed using logistic regression. A receiver operating characteristic (ROC) curve and a nomogram were constructed. The putative underlying cellular mechanisms were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and gene set enrichment analysis (GSEA). Results: Our results revealed that S100A2 expression was significantly higher in endometrial carcinoma tissue than in non-cancerous tissue at both the mRNA and protein levels. Analysis of Kaplan–Meier plotter data revealed that patients with high S100A2 expression had shorter overall survival (OS) and disease specific survival (DSS) compared with those of patients with low S100A2 expression. Multivariate Cox analysis further confirmed that high S100A2 expression was an independent risk factor for OS in patients with endometrial carcinoma. Other clinicopathologic features found to be related to worse prognosis in endometrial carcinoma included age, clinical stage, histologic grade, and tumor invasion. Importantly, ROC analysis also confirmed that S100A2 has a high diagnostic value in endometrial carcinoma. KEGG enrichment analysis and GSEA revealed that the estrogen and IL-17 signaling pathways were significantly upregulated in the high S100A2 expression group, in which estrogen response, JAK-STAT3, K-Ras, and TNFα/NF-κB were differentially enriched. Conclusions: S100A2 plays an important role in endometrial carcinoma progression and may represent an independent diagnostic and prognostic biomarker for endometrial carcinoma.

ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.