BACKGROUND: Gallbladder cancer (GBC) is a highly aggressive malignancy with limited therapeutic options and a poor prognosis. Elucidating the molecular mechanisms driving GBC progression is essential for identifying novel therapeutic targets. METHODS: Single-cell transcriptomics, high-throughput sequencing, and proteomics techniques were employed to investigate the role of the IGF2BP2-PRMT5 axis in GBC. Functional assays were conducted to assess cell proliferation, invasion, and migration, while mechanistic studies examined the impact of N6-methyladenosine (m6A) modifications and downstream signalling pathways. Furthermore, a humanised mouse model was utilised to examine the impact of this axis on immune cell infiltration and tumour immune evasion. RESULTS: IGF2BP2 was found to stabilise PRMT5 expression via m6A modifications, thereby promoting GBC cell proliferation, invasion, and migration. Mechanistically, PRMT5 activated the AKT/mTOR pathway, upregulated SREBP1, and reprogrammed lipid metabolism, leading to increased lipid synthesis and accumulation. Functional assays and in vivo experiments revealed that modulation of the IGF2BP2-PRMT5 axis significantly influenced immune cell infiltration, fostering immune evasion. CONCLUSIONS: The IGF2BP2-PRMT5 axis is critical in GBC progression by orchestrating metabolic reprogramming and immune modulation. Targeting this axis holds potential as a therapeutic strategy for combating GBC.