Background <p>Our previous study indicated that IGF2BP1 involves in the regulation of resistance in nasopharyngeal carcinoma (NPC) to paclitaxel. The objective of this study is to clarify the molecular mechanisms.</p> Methods <p>H3K4Me1 modification at the IGF2BP1 gene promoter was confirmed by ChIP. Flow cytometry was performed for cell apoptosis and ratio of CD8⁺T/PD-1 or CD8⁺T/Ki-67 double-positive cells. Immune cells infiltration was detected by immunohistochemistry. The m⁶A modification at PD-L1 mRNA was determined by MeRIP assay.</p> Results <p>H3K4Me1 modification was elevated in paclitaxel-resistant NPC cells to facilitate the IGF2BP1 expression. Inhibition of H3K4Me1 modification using MM-401 reduced the H3K4Me1 modification at IGF2BP1 gene promoter, decreased IGF2BP1 expression, promoted cell apoptosis, and suppressed cell viability in paclitaxel-resistant NPC cells. MM-401 treatment or silencing IGF2BP1 impeded paclitaxel-resistant NPC tumors growth, and reduced immune cells (CD4⁺T, CD8⁺T, and macrophages) infiltration in tumors. Moreover, in paclitaxel-resistant NPC cells, silencing IGF2BP1 inhibited PD-L1 expression. Inhibiting H3K4Me1-mediated IGF2BP1 expression resulted in an improved in the viability and proliferation of CD8⁺T cells. IGF2BP1 bound with PD-L1 mRNA. MM-401 treatment or silencing IGF2BP1 suppressed IGF2BP1-mediated m⁶A modification at PD-L1 mRNA. Meantime, in paclitaxel-resistant NPC cells, MM-401 treatment or silencing IGF2BP1 reduced glycolysis-related enzymes expression and lactic acid production. Importantly, silencing IGF2BP1-resulted decreasing in PD-L1 expression was reversed by lactate treatment.</p> Conclusion <p>Overall, silencing H3K4Me1-mediated IGF2BP1 expression suppressed the immune escapes and drug resistance of NPC cells via decreasing PD-L1 expression by reducing m⁶A modification at PD-L1 mRNA and by reducing lactic acid production.</p>