N⁶-methyladenosine modification regulates innate immune signaling and reshapes the tumor immune microenvironment: a review

Tumor development is intimately linked to the dynamic equilibrium of innate immunity, which exerts a typical “double-edged sword” effect by suppressing tumorigenesis at early stages while fostering an immunosuppressive microenvironment during chronic inflammation. Consequently, T cell-centered immune checkpoint blockade (ICB) therapies frequently encounter resistance. N⁶-methyladenosine (m⁶A), the most prevalent mRNA modification, functions as a pivotal epitranscriptomic regulatory hub that integrates oncogenic, metabolic, and microenvironmental cues through the Writers–Erasers–Readers network. Mechanistically, m⁶A bidirectionally regulates innate immune signaling pathways, including cGAS-STING, RIG-I/MDA5, NF-κB, and TLR signaling, while also shaping non-coding RNA networks that underlie viral mimicry. On the one hand, m⁶A amplifies anti-tumor immunity by promoting type I interferon signaling, dendritic cell maturation, antigen presentation, and M1-like macrophage polarization. On the other hand, tumor-hijacked m⁶A machinery promotes STING and RIG-I suppression, antigen degradation, viral mimicry silencing, M2 macrophage polarization, and immunosuppressive myeloid remodeling. Based on these mechanisms, this review proposes an m⁶A-driven immunophenotyping framework that stratifies tumors into DC-dysfunctional “cold” tumors, innate-sensing-silent tumors, and myeloid-suppressed “hot” tumors. Targeting YTHDF1, FTO/ALKBH5, or METTL3 in phenotype-specific contexts, guided by precise biomarkers, may provide a mechanism-based strategy to overcome ICB resistance. However, tumor-selective delivery and safety evaluation remain essential for clinical translation.