Work

Targeting the m6A reader YTHDF1 for overcoming cancer therapeutic resistance and enhancing tumor immunotherapy

Year: 2026

Type: article

Abstract: N6-methyladenosine (m⁶A) is a major post-transcriptional RNA modification that regulates RNA stability, translation, degradation, and immune-related gene expression. As a key m⁶A reader, YTHDF1 mainly promotes the translation of m⁶A-modified transcripts and has emerged as an important regulator of tumor progression and antitumor immunity. Increasing evidence shows that YTHDF1 is frequently upregulated in multiple cancers and contributes to tumor proliferation, metabolic reprogramming, epithelial–mesenchymal transition, stemness, ferroptosis resistance, metastasis, and therapy resistance. Beyond its tumor-cell-intrinsic roles, YTHDF1 also shapes the tumor immune microenvironment by regulating dendritic cell antigen presentation, macrophage polarization, myeloid-derived suppressor cell recruitment, T-cell activity, immune checkpoint expression, and response to immune checkpoint blockade. In this mini review, we summarize the biological functions and upstream regulatory mechanisms of YTHDF1, including transcriptional control, ubiquitination, O-GlcNAcylation, and non-coding RNA-mediated regulation. We further discuss the context-dependent roles of YTHDF1 across different cancers and immune cell populations. Although YTHDF1 often acts as an oncogenic and immunosuppressive factor, its functions are not uniform and depend on tumor type, cellular context, target transcripts, and immune status. Therapeutically, YTHDF1 inhibition may enhance tumor antigen presentation, restore CD8⁺ T-cell activity, remodel suppressive myeloid cells, and improve the efficacy of PD-1/PD-L1 blockade. However, clinical translation remains challenging because of YTH family homology, tumor heterogeneity, immune complexity, delivery barriers, and potential systemic toxicity. Future studies should focus on selective YTHDF1 inhibitors, cell-type-specific mechanisms, biomarker-guided patient selection, and rational combination strategies. Overall, YTHDF1 represents a central epitranscriptomic node linking m⁶A-dependent RNA regulation with tumor immunity and may provide new opportunities for cancer immunotherapy.

Source: Discover Oncology

DOI: 10.1007/s12672-026-05962-6

Authors: Haipeng Wang, Yi Zhang, Lingyun Li, Xiaojuan Liu

Institutions: Hunan Normal University, Changsha Hospital for Maternal and Child Health Care

Language: English

Topic: RNA modifications and cancer

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,690