METTL1-mediated tRNA m7G methylome remodeling drives macrophage M2 polarization and paclitaxel resistance in cervical cancer

OBJECTIVE: Chemoresistance remains a major obstacle to effective treatment of cervical cancer. Emerging evidence suggests that RNA methylation plays a crucial role in shaping tumor-immune interactions. However, the role of METTL1-mediated tRNA m7G modification in macrophage polarization and drug resistance is largely unexplored. Trac-seq was performed to characterize tRNA m7G remodeling. Trac-seq revealed extensive remodeling of tRNA m7G methylome following METTL1 overexpression, with selective hypo- and hypermethylation across distinct tRNAs. Single-cell analysis identified reduced NLRP3 expression in METTL1-high macrophages, and METTL1 overexpression suppressed pyroptosis, whereas WDR4 depletion produced opposing effects and partially attenuated METTL1-mediated changes in macrophages. CONCLUSION: METTL1 promotes M2-like macrophage polarization and paclitaxel resistance in cervical cancer, accompanied by extensive remodeling of the tRNA m7G methylome, providing a potential epitranscriptomic link between macrophage reprogramming and chemoresistance.