tRNA m2G methyltransferase complex THUMPD3-TRMT112 promotes pancreatic cancer progression and autophagy via modulating TFEB translation

Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11–2 (TRMT112) complex has been identified as a tRNA m2G methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA m2G modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired m2G modification of tRNALeu(CAG), thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 m2G tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-025-02540-2.