RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

Area of Science:

• Immunology
• Epigenetics
• Cancer Biology

Background:

• N6-methyladenosine (m6A) is a crucial mRNA modification involved in diverse biological processes.
• The specific roles of m6A modification in macrophages remain largely unexplored.
• Understanding m6A's function in macrophages is vital for cancer research.

Purpose of the Study:

• To investigate the function of METTL3-mediated m6A modification in myeloid cells within the tumor microenvironment.
• To elucidate the molecular mechanisms by which m6A affects tumor growth, metastasis, and immune cell infiltration.
• To assess the impact of METTL3 deficiency on the efficacy of cancer immunotherapy.

Main Methods:

• Utilized Mettl3-deficient mice with ablation in myeloid cells to study tumor progression in vivo.
• Employed m6A sequencing to identify global changes in m6A modification upon METTL3 loss.
• Analyzed immune cell infiltration (tumor-associated macrophages and regulatory T cells) using flow cytometry and immunohistochemistry.
• Investigated downstream signaling pathways including NF-kB, STAT3, and ERK.

Main Results:

• Ablation of Mettl3 in myeloid cells significantly promoted tumor growth and metastasis in vivo.
• Mettl3-deficient mice exhibited increased infiltration of M1/M2-like tumor-associated macrophages and regulatory T cells.
• Loss of METTL3 impaired YTHDF1-mediated translation of SPRED2, leading to enhanced NF-kB and STAT3 activation via the ERK pathway.
• The therapeutic efficacy of PD-1 checkpoint blockade was significantly attenuated in Mettl3-deficient mice.

Conclusions:

• METTL3-mediated m6A modification in myeloid cells plays a critical role in regulating tumor immunity and progression.
• METTL3 deficiency promotes tumor growth and metastasis by modulating macrophage polarization and T cell infiltration.
• The identified molecular pathway involving METTL3, YTHDF1, SPRED2, and NF-kB/STAT3 offers insights into tumor immune evasion.
• METTL3 represents a promising therapeutic target for enhancing the effectiveness of cancer immunotherapy, particularly PD-1 blockade.