METTL3 Methylation Induces Decay of Endogenous Retroelement Transcripts to Promote Tumor Immune Evasion

Colorectal cancer progression and recurrence persist as major clinical challenges. Emerging evidence underscores that cross-talk between malignant cells and the immunosuppressive microenvironment facilitates tumor relapse, and elucidating the mechanistic details of this cross-talk could help guide the development of improved therapies. In this study, we identified dimethylation of lysine 513 (K513) on methyltransferase-like 3 (METTL3) as a key modification associated with colorectal cancer progression and recurrence. Mechanistically, SETD1A catalyzed METTL3 K513 methylation, enhancing its binding affinity to S-adenosylmethionine and augmenting RNA N6-methyladenosine deposition. METTL3 methylation suppressed endogenous retroelements expression, leading to impaired type I IFN responses and tumor immune evasion. Fluorouracil induced an E2F4/SETD1A/METTL3 regulatory axis, wherein E2F4 self-regulation activated SETD1A to drive METTL3 methylation. Targeting this axis through pharmacologic inhibition of E2F4 or genetic disruption of METTL3 methylation, in combination with immune checkpoint blockade (ICB), significantly suppressed tumor growth. These findings unveil a methylation-dependent regulatory mechanism that reshapes the tumor immune microenvironment, offering a therapeutic strategy for colorectal cancer. Significance: Suppression of endogenous retroelements and type I interferon signaling mediated by E2F4/SETD1A-induced METTL3 K513 methylation can be targeted to restore antitumor immunity and enhance responsiveness to immune checkpoint blockade in colorectal cancer.