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 cancers (CRCs) therapy, yet the majority of microsatellite-stable (MSS) CRCs remain refractory due to insufficient tumor-immune cell crosstalk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. Here, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in CRC, 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 non-inflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized MSS CRCs to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1'simpact on tumor-immune interactions, and showed that it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in CRC.