Alternative splicing of NUMB correlates with tumor immune evasion and metabolic adaptation.

Abstract

Alternative splicing of the NUMB gene at exon 9 generates protein isoforms linked to tumor growth and metastasis, but its impact on the tumor immune microenvironment remains unclear. Using RNA sequencing data from over 5,000 tumors across 16 cancer types, including breast cancer subtypes, we found that tumors with high NUMB exon 9 inclusion exhibit lower expression of immune-related genes, reduced immune cell infiltration, and decreased cytolytic activity, consistent with an immune "cold" phenotype. This pattern was consistent across multiple cancer types and breast cancer subtypes. Additionally, exon 9-high tumors showed evidence of increased oxidative phosphorylation, suggesting metabolic adaptations that support tumor progression. These findings identify NUMB exon 9 inclusion as a potential biomarker of immune evasion and highlight opportunities for patient stratification and targeted therapies based on NUMB exon 9 inclusion levels.