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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.