Tumor cell-intrinsic NSUN2 deficiency reprograms macrophages to sensitize non-small cell lung cancer to EGFR inhibitors by reversing immune evasion.

Despite EGFR-tyrosine kinase inhibitors (EGFR-TKI) have improved outcomes in non-small cell lung cancer (NSCLC), acquired resistance remains a challenge. While RNA methylation has been implicated in drug resistance, its role in EGFR-TKI resistance through immune regulation remains unexplored. Here, we established gefitinib- and osimertinib-resistant NSCLC cells and found that NSUN2 knockdown did not affect proliferation or drug sensitivity under immunodeficient conditions. Conversely, under immunocompetent conditions, NSUN2 knockdown suppressed proliferation and restored EGFR-TKI sensitivity by converting 'cold' resistant tumors to 'hot' tumors. Mechanistically, NSUN2 knockdown promoted macrophage migration and chemokine expression, and enhanced M0-to-M1 polarization, with opposite effects observed upon NSUN2 overexpression. Integrative RNA Bis-seq and RNA-seq identified the E3 ubiquitin ligase TRIM29 as a key target downregulated upon NSUN2 knockdown and upregulated upon overexpression. Consistently, TRIM29 depletion phenocopied NSUN2 knockdown by promoting M1 polarization and macrophage migration. These findings identify NSUN2 as a driver of immune evasion and acquired EGFR-TKI resistance through epigenetic regulation of macrophage infiltration and polarization.