E3 ligase FBXW7 restricts M2-like tumor-associated macrophage polarization by targeting c-Myc

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• FBXW7 (F-box and leucine-rich repeat protein WWOX domain-containing protein 7) is an E3 ubiquitin ligase crucial for degrading oncoproteins in cancer cells.
• The role of FBXW7 in macrophages and the tumor immune microenvironment remains largely unexplored.
• Tumor-associated macrophages (TAMs) significantly influence tumor progression and the immune response.

Purpose of the Study:

• To investigate the function of FBXW7 in macrophage polarization within the tumor immune microenvironment.
• To elucidate the impact of FBXW7 on M2-like TAM polarization and its role in limiting tumor progression.

Main Methods:

• Utilized myeloid FBXW7-deficient mice and Lewis lung carcinoma cells (LLCs) for in vivo tumor growth studies.
• Performed in vitro experiments stimulating FBXW7-knockout macrophages with LLCs supernatant.
• Investigated the underlying molecular mechanism involving c-Myc degradation via the ubiquitin-proteasome system.

Main Results:

• Myeloid FBXW7 deficiency led to increased M2-like TAMs and aggravated tumor growth in mice.
• FBXW7-knockout macrophages exhibited enhanced M2 polarization and promoted cancer cell growth in vitro.
• FBXW7 was confirmed to inhibit M2-like TAM polarization by mediating c-Myc degradation.

Conclusions:

• FBXW7 plays a critical role in suppressing M2-like TAM polarization, thereby limiting tumor progression.
• FBXW7 deficiency promotes a pro-tumorigenic M2 TAM phenotype.
• Targeting FBXW7 may offer novel strategies for cancer immunotherapy by modulating TAM polarization.