hnRNPA2B1 sustains antitumor T cell immunity and enhances cancer immunotherapy through IDR-dependent stabilization of chromatin-regulatory transcripts

Abstract

T cell exhaustion within the tumor microenvironment poses a major barrier to effective cancer immunotherapy, yet the epigenetic mechanisms that preserve functional states of tumor-infiltrating T cells remain incompletely understood. Here, using an in vivo CRISPR screen, we identify heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) as a regulator of CD8+ T cell fitness. Transcriptomic analyses of cancer patient cohorts reveal that hnRNPA2B1 is preferentially enriched in a proliferative, intermediate exhausted T cell subset associated with favorable clinical outcomes. Genetic ablation of hnRNPA2B1 in CD8+ T cells accelerates terminal exhaustion, impairs antitumor immunity, and diminishes responsiveness to immune checkpoint blockade. Mechanistically, hnRNPA2B1 forms nuclear puncta and stabilizes RNAs involved in chromatin organization, thereby maintaining chromatin accessibility that restrains exhaustion-associated programs while preserving proliferative and cytotoxic potential. Together, these findings establish hnRNPA2B1 as an RNA-mediated epigenetic regulator sustaining functional exhausted T cell states in tumors.