YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8⁺ T cells

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Tumor-associated macrophages (TAMs) are crucial in the tumor microenvironment (TME), but their precise mechanisms of action are not fully understood.
• Understanding how TAMs influence cancer progression is vital for developing effective cancer therapies.

Purpose of the Study:

• To investigate the role of the N6-methyladenosine reader YTHDF2 in regulating TAM functions.
• To explore the potential of targeting YTHDF2 in TAMs for cancer immunotherapy.

Main Methods:

• Investigated YTHDF2's role in TAMs using genetic deficiency models.
• Analyzed the impact of YTHDF2 on TAM phenotype, antigen presentation, and CD8+ T cell responses.
• Utilized Toll-like receptor 9 agonist-conjugated small interfering RNA for targeted YTHDF2 inhibition in TAMs.

Main Results:

• YTHDF2 deficiency in TAMs suppressed tumor growth by promoting an antitumoral phenotype and enhancing antigen cross-presentation.
• YTHDF2 deficiency reprogrammed TAMs via the interferon-gamma-STAT1 signaling pathway.
• Interleukin-10-STAT3 signaling regulated YTHDF2 expression in TAMs.
• Targeted YTHDF2 inhibition in TAMs enhanced CD8+ T cell-mediated antitumor immunity and improved PD-L1 antibody therapy efficacy.

Conclusions:

• YTHDF2 plays a critical role in orchestrating TAM functions within the TME.
• Inhibiting YTHDF2 in TAMs represents a promising strategy to enhance cancer immunotherapy and restrain tumor growth.