The Prof. YAN Xiyun's group at the Institute of Biophysics, Chinese Academy of Sciences, published an article titled "A subpopulation of CD146⁺ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome" in the journal of Cellular & Molecular Immunology on June 12, 2023. The study reported a subtype of CD146⁺ macrophages in the tumor microenvironment, providing a new strategy for macrophage-based tumor immunotherapy.

Although immunotherapy is the most promising treatment for cancer, the complexity of the tumor microenvironment severely limits its effectiveness. Tumor-associated macrophages (TAMs), which account for a significant proportion of immune cells in the tumor microenvironment, are important targets for tumor immunotherapy due to their high heterogeneity and strong plasticity. Analyzing TAMs' phenotype and function in-depth and elucidating their mechanisms of action can help design new strategies for tumor treatment.

The Yan's group previously reported the role and regulatory mechanism of CD146 molecule in the pro-inflammatory polarization process of macrophages from different sources (peripheral infiltration and adipose tissue settlement) in the high-fat microenvironment (Cell Research, 2017, and Advanced Science, 2022). Considered the important role of macrophages in tumor immunotherapy in the tumor microenvironment, they next to explore the effect of this subpopulation of macrophages on tumor development.

By using mouse tumor models and clinical tumor samples, they found CD146⁺ macrophages in the tumor microenvironment, and this group of cells mainly existed at the margin of the tumor tissue, exerting the antitumor effect of M1-like macrophages. With the progression of the tumor, CD146⁺ macrophages activated the STAT3 signal under the domestication of the tumor microenvironment, which inhibited CD146 expression, leading this group of macrophages gradually to lose CD146 expression and display the M2-like phenotype. The downregulation of CD146 led to the activation of JNK signal, which then upregulated the expression of MDSC-recruiting associated factors and TMEM176B, the later which inhibits the activation of inflammasome. The comprehensive effect caused by the downregulation of CD146 further inhibited the antitumor effect of T cells, thereby promoting tumor progression (Figure 1). This study reveals the changing pattern and mechanism of CD146⁺ macrophages in the tumor microenvironment. Considering that CD146 is a therapeutic target for tumor blood vessels, this study adopted a combined tumor treatment strategy that uses functional antibody AA98 against CD146 in combination with TMEM176B inhibitor, which shows better antitumor effect than using AA98 alone.

Figure. The changing pattern and mechanism of CD146⁺ macrophages in the tumor microenvironment

Article link: https://doi.org/10.1038/s41423-023-01047-4

Contact: DUAN Hongxia

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: cherryshoen@ibp.ac.cn

（Reported by Prof. YAN Xiyun's group）