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

TL;DR

This study shows how HNRNPA2B1 helps non-small cell lung cancer cells avoid immune detection and resist cell death through m6A modification and lactate production.

Contribution

The study reveals a novel mechanism by which HNRNPA2B1 promotes immune escape and ferroptosis resistance in NSCLC via m6A modification of LDHA mRNA.

Findings

HNRNPA2B1 high-expression impairs CD8+ T cell-mediated killing and promotes immune escape in NSCLC.

HNRNPA2B1 stabilizes LDHA mRNA, increases lactate accumulation, and reduces IFN-γ secretion by CD8+ T cells.

IFN-γ induces ferroptosis in NSCLC cells, but this is counteracted by HNRNPA2B1 activity.

Abstract

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.

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