The Dual Role of Folate Metabolism in Colorectal Cancer: Bridging Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms, Molecular Subtypes and Precision Prevention

Abstract

Colorectal cancer (CRC) exhibits complex heterogeneity driven by the interplay of genetic, metabolic, and microenvironmental factors. Folate metabolism, essential for nucleotide synthesis and epigenetic regulation, paradoxically influences CRC pathogenesis: deficiency increases initiation risk, while excess supplementation may accelerate established tumors. Central to this duality is methylenetetrahydrofolate reductase (MTHFR), whose polymorphisms (e.g., C677T, A1298C) modulate folate flux, altering DNA methylation-nucleotide synthesis balance in a context-dependent manner. Emerging evidence suggests that MTHFR variants interact with Consensus Molecular Subtypes—CMS1 (microsatellite instability), CMS3 (metabolic dysregulation), CMS2/4 (WNT/stromal-driven)—to dictate divergent folate dependencies. For instance, CMS1 tumors may exploit folate for immune evasion via adenosine signaling, whereas CMS2/4 subtypes rely on folate-mediated epigenetic reprogramming. However, current prevention strategies neglect these subtype-specific vulnerabilities, treating CRC as a monolithic entity. This review synthesizes evidence from Mendelian randomization, preclinical models, and subtype-stratified trials to propose three critical advances: (1) Subtype-Driven Folate; (2) Dependency Biomarker Integration; (3) Microenvironment Crosstalk.