Immunotherapy is the most promising modality in the current field of tumor therapy. However, the complexity of the tumor microenvironment greatly curtails the effectiveness of tumor therapy. Tumor-associated macrophages (TAMs), which are the most abundant immune cells in the tumor microenvironment, have become an important target for tumor immunotherapy due to their high heterogeneity and strong plasticity. In-depth analysis of the cellular phenotype and function of TAMs and elucidation of their mechanism of action can help to design new tumor therapeutic strategies.

Recently, some researchers have revealed the changing law and mechanism of action of CD146+ macrophages in the tumor microenvironment. Therefore, Creative Biolabs shares the interesting roles and potential mechanisms of CD146+ macrophage subpopulations, providing new insights for tumor therapy targeting TAM.

The Diversity of Macrophages

Macrophages are known for their ability to polarize into different phenotypes, with classically activated (M1) and alternatively activated (M2) being the most well-defined states. However, the traditional M1/M2 paradigm fails to capture the full complexity of macrophage heterogeneity.

Emerging evidence suggests the existence of distinct macrophage subpopulations within tissues, characterized by unique surface markers, transcriptional profiles, and functional properties. CD146+ macrophages have emerged as a fascinating subpopulation with distinct characteristics and functions.

CD146+ Macrophages in the Tumor Microenvironment

A study demonstrated the existence of a population of CD146+ macrophages in the tumor microenvironment and found that this population of cells was mainly located in the marginal parts of tumor tissues, exerting the anti-tumor effect of M1-like macrophages. Researchers initially explored the changing pattern of CD146+ macrophages in the tumor microenvironment and found that

Fig. 1 Changing law and mechanism of action of CD146+ macrophages in the tumor microenvironment. (Jing L, et al., 2023)

• As the tumor progresses, this population of macrophages is domesticated by the tumor microenvironment to upregulate STAT3 signaling, which inhibits CD146 expression, resulting in a progressive loss of CD146 in this population of cells, which exhibits an M2-like phenotype.
• Down-regulation of CD146 leads to up-regulation of JNK signaling, which in turn up-regulates the expression of MDSC-recruitment-associated chemokines and TMEM176B, which is an inhibitory molecule for macrophage inflammatory vesicle activation. The combined effect of CD146 down-regulation further inhibits the anti-tumor effects of T cells, thus promoting tumor progression.

Anti-Tumor Strategies Based on Tumor-Associated Macrophages

There is growing evidence that targeting TAMs in personalized medicine can enhance the anti-tumor effects of chemotherapy and immunotherapy.

• In early stages, TAMs exhibit an anti-tumor (or M1-like) phenotype, which allows them to clear tumor cells.
• However, as tumorigenesis progresses, TAMs shift to a pro-tumor (or M2-like) phenotype and contribute to a microenvironment suitable for tumor growth, survival, metastasis, and angiogenesis.

However, there is limited knowledge about the phenotypic and functional heterogeneity of TAMs, and further studies are needed to elucidate their phenotypes and functions in order to develop new cancer treatment strategies.

Creative Biolabs provides research services to help explore the mechanisms of CD146 macrophages as an anti-tumor population and the development of CD146-based anti-tumor therapeutic strategies. If you want to know more about professional services, please feel free to contact us.

Reference

1. Jing L, et al. A subpopulation of CD146+ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome. Cellular & Molecular Immunology, 2023: 1-16.