Tumor-intrinsic NSUN2 orchestrates immunosuppression in lung adenocarcinoma via the m5C-HDAC8-CCL5 axis.

BACKGROUND: Insufficient T-cell infiltration is a major barrier to the efficacy of immune checkpoint inhibitors (ICIs) in lung adenocarcinoma (LUAD). We aimed to investigate how the tumor-intrinsic m5C methyltransferase NSUN2 shapes the immune landscape of LUAD. METHODS: Nsun2 conditional knockout mice and syngeneic mice models were employed. Single-cell RNA sequencing (scRNA-seq) and m5C sequencing were performed to elucidate the downstream pathway regulated by NSUN2. LUAD specimens from patients receiving neoadjuvant immunotherapy were used to assess the correlation between NSUN2 expression and immune infiltration. RESULTS: Elevated tumoral NSUN2 expression was correlated with a marked lack of CD8+ T-cell infiltration and immunotherapy resistance. Mechanistically, NSUN2 enhances the translation of histone deacetylase HDAC8 in an m⁵C-YBX1-dependent manner, which in turn directly represses the transcription of the chemoattractant CCL5, thereby impairing CD8+ T-cell recruitment into the tumor. NSUN2 depletion reversed this immunosuppressive axis and converted immunologically "cold" tumors into "hot". Tumor-targeted liposomes loaded with the NSUN2 inhibitor synergized with anti-PD-1 therapy to induce significant tumor regression. CONCLUSIONS: Our findings identify NSUN2 as a critical orchestrator of T-cell exclusion in LUAD. It serves as both a candidate predictive biomarker for ICI failure and a promising druggable target. Targeting NSUN2 offers a potential strategy to overcome immunotherapy resistance and improve clinical outcomes in LUAD patients.