METTL16 regulates metabolism， metastasis and therapy response in cancer through m6A dependent and m6A independent mechanisms

N6-methyladenosine (m6A) modification critically regulates RNA metabolism and post-transcriptional gene expression. METTL16, a non-canonical m6A methyltransferase, orchestrates a multilayered regulatory network beyond U6 snRNA methylation, including SAM homeostasis and substrate-specific epitranscriptomic control. Recent findings reveal that lactylation at lysine 229 modulates METTL16 activity to regulate cuproptosis, while METTL16-dependent m6A modification of GPX4 underlies tyrosine kinase inhibitor resistance in non-small cell lung cancer. This review systematically analyzes METTL16's roles across nine major cancer types, encompassing digestive system tumors (hepatocellular carcinoma, colorectal cancer, pancreatic ductal adenocarcinoma), female reproductive cancers (breast and ovarian), hematological malignancies (acute myeloid leukemia), urological cancers (bladder cancer), osteosarcoma, and lung cancer. METTL16 facilitates metastasis and modulates anti-tumor immunity. In acute myeloid leukemia, METTL16 drives leukemogenesis through a novel MXD4-MYC axis, providing a strategy to indirectly target the oncogenic MYC. METTL16-mediated regulation of S-adenosylmethionine connects epitranscriptomic modification with cellular metabolism, while it also modulates tumor immune microenvironment composition and immunotherapy response. Preclinical evidence reveals that first-in-class aminothiazolone inhibitors disrupt the METTL16-RNA interaction and lipid nanoparticle-encapsulated siRNA systems silence METTL16 in triple-negative breast cancer models. Notably, METTL16 is predominantly oncogenic across cancer types but tumor-suppressive in bladder cancer, underscoring the need for context-specific targeting. This gene-centric review consolidates current regulatory networks of METTL16, integrating recent findings on lactylation-dependent regulation and immune modulation, and identifies critical targets for anti-metastatic precision therapy.