The tumor-intrinsic role of the m⁶A reader YTHDF2 in regulating immune evasion

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Tumors employ diverse strategies to evade immune system detection and destruction.
• YTH domain-containing family protein 2 (YTHDF2) is an m⁶A-modified mRNA reader protein implicated in cellular regulation.

Purpose of the Study:

• To investigate the role of tumoral YTHDF2 in tumor immune evasion.
• To explore YTHDF2 as a potential therapeutic target for cancer immunotherapy.

Main Methods:

• Utilized immunocompetent tumor models to assess the impact of tumoral YTHDF2 loss on tumor growth and survival.
• Investigated the mechanisms of immune cell recruitment and function, including macrophage polarization and CD8+ T cell metabolism.
• Examined the effect of IFN-γ on YTHDF2 degradation and tumor cell sensitivity to T cell-mediated cytotoxicity.
• Identified and tested a small molecule compound targeting YTHDF2 degradation in combination with immune checkpoint inhibitors.

Main Results:

• Loss of tumoral YTHDF2 significantly inhibited tumor growth and prolonged survival.
• YTHDF2 deficiency enhanced macrophage recruitment via CX3CL1 and improved CD8+ T cell mitochondrial respiration by reducing tumor glycolysis.
• Tumoral YTHDF2 deficiency promoted inflammatory macrophage polarization and antigen presentation under IFN-γ stimulation.
• IFN-γ induced autophagic degradation of YTHDF2, increasing tumor cell susceptibility to CD8+ T cell cytotoxicity.
• A novel small molecule targeting YTHDF2 degradation demonstrated potent antitumor effects, especially when combined with anti-PD-1/PD-L1 antibodies.

Conclusions:

• YTHDF2 acts as a critical tumor-intrinsic regulator orchestrating immune evasion.
• Targeting YTHDF2 degradation represents a promising strategy to enhance cancer immunotherapy efficacy, particularly in combination with immune checkpoint inhibitors.