Macrophages carry metformin to enhance the anti-tumor effect of PD-1

Macrophages carry metformin to enhance the anti-tumor effect of PD-1. Nature: Let macrophages carry metformin to enhance the anti-tumor effect of PD-1。

Metformin effectively reverse-polarizes M2 tumor-associated macrophages (TAM) to M1 phenotype through AMPK-NF-κB signaling pathway, thereby inhibiting tumor growth and metastasis.

Immune checkpoint blocking therapy has become one of the most popular immunotherapies today. This therapy has significantly changed the current pattern of cancer treatment, and PD-1 immunoblocking therapy is the most typical representative of it. Although anti-PD-1 immunotherapy has made good progress in tumor treatment, there is still a problem of low response rate in the treatment of many solid tumors.

The main reasons leading to PD-1 antibody tumor immunotherapy tolerance are:

1. Insufficient infiltration of T lymphocytes in tumor tissues, so-called “cold tumors”;

2. The tumor immunosuppressive microenvironment composed of immunosuppressive cells such as M2 tumor-associated macrophages (TAM), bone marrow-derived suppressive cells (MDSC), regulatory T cells (Treg), etc. weakened its anti-tumor immune response ；

3. Physiological barriers such as abnormal vascular structure, high interstitial hydraulic pressure and dense extracellular matrix hinder the effective accumulation and deep penetration of PD-1 antibody in tumor tissue.

How to solve the above problems to enhance the therapeutic effect of PD-1 antibody faces many challenges. Previous studies have confirmed that M2 tumor-associated macrophages (TAM) play an important role in promoting tumor growth, angiogenesis, tumor metastasis, and immune escape.

Metformin (Metfromin) is widely used in the treatment of diabetes due to its good hypoglycemic effect, few side effects and low cost. In addition, a large number of studies have shown that metformin can regulate tumor metabolism, block tumor cell cycle, inhibit angiogenesis and kill cancer stem cells by activating 5′-adenosine monophosphate (AMP) activated protein kinase (AMPK).

On January 19, 2021, the team of Professor Yang Xiangliang and Professor Gan Lu of Huazhong University of Science and Technology, and the team of Professor Huang Bo of the Chinese Academy of Medical Sciences published an online title: Boosting Anti-PD-1 Therapy with Metformin-Loaded Macrophage in Nature Communications. -Research papers on Derived Microparticles.

The research team constructed mannose (Man) modified macrophage-derived microparticles (MPs) and loaded with metformin (Met). The drug-loaded microparticles (Met@Man-MPs) can effectively target tumor M2 tumor-associated macrophages (TAM) and promote the reverse polarization of M2 tumor-associated macrophages (TAM) into M1 type with anti-tumor activity. Effectively inhibit tumor growth.

In various anti-tumor experiments of tumor-bearing animal models, it has been proved that Met@Man-MPs can effectively improve the therapeutic effect of PD-1 antibody and form long-term anti-tumor immune memory. This research provides a new strategy for improving the therapeutic effect of PD-1 antibody.

Recent studies have shown that metformin effectively reverse-polarizes M2 tumor-associated macrophages (TAM) to M1 phenotype through AMPK-NF-κB signaling pathway, thereby inhibiting tumor growth and metastasis.

However, how to achieve the targeted delivery of metformin to M2 tumor-associated macrophages (TAM) to further improve the effect of cancer treatment is still facing a huge challenge.

The research team took advantage of the natural tumor-targeting properties of macrophages and the high expression of mannose receptors in M2 tumor-associated macrophages (TAM) to construct mannose (Man)-modified macrophage-derived microparticles (MPs). ) And loaded with metformin (Met).

The drug-loaded microparticles (Met@Man-MPs) can effectively target tumor M2 tumor-associated macrophages (TAM) and promote the reverse polarization of M2 tumor-associated macrophages (TAM) into M1 type with anti-tumor activity. Effectively inhibit tumor growth.

Met@Man-MPs can effectively improve the tumor immune microenvironment, using its reverse polarization into M1 tumor-associated macrophages (TAM) secreted cytokines TNF-α, etc. to promote the recruitment of CD8+ T cells, and reduce the inhibitory properties of bone marrow origin The number of cells (MDSC) and regulatory T cells (Treg); more importantly, Met@Man-MPs carry matrix metalloproteinases (MMPs) derived from macrophages, which can effectively degrade tumor extracellular matrix and increase CD8+ T Cells infiltrate deep into tumor tissues, and PD-1 antibody enriches and penetrates deep into tumor tissues.

In various anti-tumor experiments of tumor-bearing animal models, it has been proved that Met@Man-MPs can effectively improve the therapeutic effect of PD-1 antibody and form long-term anti-tumor immune memory. This research provides a new strategy for improving the therapeutic effect of PD-1 antibody.

(source:internet, reference only)

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