Pan-Cancer Analysis Identifies SNORA12 as a Prognostic Biomarker and Demonstrates Its Role in Upregulating TIGIT in Osteosarcoma

Background: Small nucleolar RNAs (snoRNAs) are emerging regulators of tumorigenesis, yet their pan-cancer landscape and immunological roles remain poorly defined. This study investigates the expression pattern, prognostic significance, and immune correlation of SNORA12 across cancers, with mechanistic validation in osteosarcoma. Methods: We integrated RNA-seq data from the TCGA, TARGET, and GTEx databases to evaluate SNORA12 expression and its prognostic value using Cox regression and Kaplan–Meier analyses (progression-free survival, PFS). The correlation between SNORA12 and the tumor immune microenvironment was assessed using six independent algorithms (TIMER, EPIC, CIBERSORT, IPS, MCP-counter, xCELL). In vitro, the regulatory effect of SNORA12 on the immune checkpoint TIGIT was validated by overexpression and knockdown experiments in osteosarcoma cell lines (SW1353, U2OS) and NK cells. Results: SNORA12 expression exhibited significant tumor-type specificity. High SNORA12 expression was associated with poor prognosis in glioma (HR = 1.31, p = 0.006) but favorable outcomes in pancreatic (HR = 0.51, p = 0.01) and breast cancer (HR = 0.56, p = 0.02). Immunologically, SNORA12 showed robust positive correlations with CD8+ T cell infiltration in thyroid carcinoma (THCA) and lung adenocarcinoma (LUAD) across multiple algorithms. Notably, SNORA12 expression was positively correlated with m6A modifiers METTL3 and YTHDF1, and negatively correlated with the demethylase FTO. Experimentally, overexpression of SNORA12 in osteosarcoma cells and primary NK cells significantly upregulated TIGIT at both the mRNA and protein levels, while SNORA12 knockdown in NK92 cells reduced TIGIT expression. Conclusions: This pan-cancer analysis positions SNORA12 as a tumor type-specific prognostic biomarker and reveals its novel role as a positive regulator of TIGIT in osteosarcoma, offering a potential mechanistic link between snoRNA dysregulation and immune evasion.