HNRNPA2B1 confers immune escape of non-small cell lung cancer through targeting lactate/ferroptosis

Immune escape and ferroptosis resistance contribute to non-small cell lung cancer (NSCLC) carcinogenesis. This study aimed to investigate the role of N⁶-methyladenosine (m⁶A) reader heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) in NSCLC immune escape and ferroptosis resistance. HNRNPA2B1 expression was clinically elevated both in the NSCLC samples and single-cell transcriptome sequencing (scRNA-Seq). In vitro co-culture with activated CD8⁺ T cells, HNRNPA2B1 high-expression hampered the CD8⁺ T cell-mediated killing effect and accelerated the immune escape. Besides, the enforced HNRNPA2B1 high-expression alleviated the ferroptosis. Furthermore, HNRNPA2B1 targeted the LDHA mRNA m⁶A modified site to enhance LDHA mRNA stability and lactate accumulation, thereby assisted NSCLC cells to evade CD8⁺ T antitumor immunity and reduced IFN-γ secretion by CD8⁺ T. Furthermore, IFN-γ could stimulate ferroptosis of NSCLC cells. Taken together, these findings revealed an important role for HNRNPA2B1 on NSCLC immune escape and ferroptosis resistance, which provided novel insight into m⁶A modification in NSCLC.