Toxicological Implications of m6A Dysregulation: SH3PXD2A-AS1-Driven PD-L1 Overexpression Promotes Immune Evasion in
Siyan Wu1, Juan Chen1, Yu Han1
1Department of Respiratory and Critical Care Medicine, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, China.
Abstract:
The lncRNA SH3PXD2A-AS1 drives therapy resistance in non-small cell lung cancer (NSCLC) through m6A-mediated PD-L1 overexpression, representing a novel molecular toxicology paradigm. In the present work, the functional significance of SH3PXD2A-AS1 in orchestrating immune escape and malignant progression of NSCLC was systematically examined. Integrating TCGA analyses with cell and mouse studies, we found that SH3PXD2A-AS1 was elevated in NSCLC and associated with features of an immunosuppressive tumor microenvironment. Multi-omics profiling, RNA pull-down/RIP, and promoter-reporter assays revealed that SH3PXD2A-AS1 interacts with the transcription factor MYBL2 to drive transcriptional activation of WTAP, a core component of the m6A writer complex. This axis enhanced m6A modification of PD-L1 mRNA, stabilizing PD-L1 and dampening CD8+ T-cell responses. Silencing SH3PXD2A-AS1 reduced MYBL2/WTAP/PD-L1 signaling, decreased malignant phenotypes in vitro, and restored antitumor T-cell activity in humanized mouse models, whereas enforced MYBL2 or WTAP expression counteracted these effects. Collectively, these findings define an lncRNA-transcription factor-epitranscriptomic checkpoint that sustains PD-L1-mediated immune escape in NSCLC, and nominate SH3PXD2A-AS1 and its MYBL2/WTAP partners as potential biomarkers and therapeutic targets to improve responses to immune checkpoint inhibition.
Insights
The long non-coding RNA SH3PXD2A-AS1 promotes immune evasion in non-small cell lung cancer (NSCLC) by increasing PD-L1. Targeting this pathway may improve immunotherapy responses.
Area of Science:
- Molecular Oncology
- Immunology
- Cancer Biology
Background:
- Non-small cell lung cancer (NSCLC) exhibits immune escape mechanisms contributing to therapy resistance.
- Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cancer progression and immune modulation.
Purpose of the Study:
- To investigate the functional role of lncRNA SH3PXD2A-AS1 in NSCLC immune escape and malignant progression.
- To elucidate the molecular mechanisms by which SH3PXD2A-AS1 influences the tumor microenvironment and T-cell responses.
Main Methods:
- TCGA data analysis, cell-based assays, and mouse models were employed.
- Multi-omics profiling, RNA pull-down, RIP assays, and promoter-reporter assays were performed.
- Investigated the interaction between SH3PXD2A-AS1, MYBL2, WTAP, and PD-L1 expression.
Main Results:
- SH3PXD2A-AS1 is upregulated in NSCLC and linked to an immunosuppressive tumor microenvironment.
- SH3PXD2A-AS1 interacts with MYBL2 to activate WTAP, enhancing m6A modification and stabilization of PD-L1 mRNA.
- Silencing SH3PXD2A-AS1 reduced PD-L1, decreased malignancy, and restored anti-tumor T-cell activity in vivo.
Conclusions:
- SH3PXD2A-AS1 acts as a crucial lncRNA-transcription factor-epitranscriptomic checkpoint driving PD-L1-mediated immune escape in NSCLC.
- SH3PXD2A-AS1, MYBL2, and WTAP are potential biomarkers and therapeutic targets to enhance responses to immune checkpoint inhibitors in NSCLC.
