TOX: A Potential New Immune Checkpoint in Cancers by A Pan-Cancer Analysis

Abstract Background TOX (Thymocyte Selection-Associated HMG BOX) belongs to a family of transcription factors with a conserved high mobility group box (HMG-box) domain. Research indicates that TOX is involved in tumor development and T cell exhaustion. This study used data from The Cancer Genome Atlas (TCGA) to evaluate TOX expression across cancers. Methods TOX expression was analyzed using RNAseq data from TCGA and the Genotype-Tissue Expression (GTEx) database. Genetic alterations and protein levels were assessed via Human Protein Atlas (HPA), GeneCards, and String databases. Prognostic significance was determined using Kaplan-Meier analysis and univariate Cox regression. Enrichment analysis was performed using the "clusterProfiler" R package. The relationship between TOX and immune cell infiltration was analyzed via TIMER2 and "CIBERSORT." Differences in TOX expression between cancerous and adjacent normal tissues were confirmed using immunohistochemistry. Results TOX expression varied across TCGA cancer types, with high expression in gliomas and lymphoma and low expression in other cancers. Genetic alterations and protein levels correlated with cancer prognosis and were linked to immune pathways, cell infiltration, and checkpoints. Significant differences in TOX expression between cancerous and adjacent normal tissues were confirmed. Conclusions TOX is a promising biomarker for cancer, likely playing a role in regulating the immune microenvironment and providing opportunities for novel targeted therapies.