Data from HNRNPA2B1 Orchestrates Immune Evasion in Colorectal Cancer by Rewiring Tumor–Immune Cell Interactions and Suppressing CD8+ T-cell Infiltration

Abstract Immune checkpoint blockade (ICB) has transformed colorectal cancer therapy, yet the majority of microsatellite-stable colorectal cancers remain refractory because of insufficient tumor–immune cell cross-talk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. In this study, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in colorectal cancer, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10–Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a noninflamed (“cold”) tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell–mediated tumor clearance, and sensitized microsatellite-stable colorectal cancers to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1’s impact on tumor–immune interactions, and it strongly correlated with immune infiltration, epithelial–mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in colorectal cancer.