Nat Commun: Let macrophages carry metformin, enhancing PD-1 anti-tumor effect

Immuno-checkpoint blocking therapy has become one of the most popular immunotherapy therapies today, which has dramatically changed the current pattern of cancer treatment, and PD-1 immuno-blocking therapy is the most typical representative of it.
although anti-PD-1 immunotherapy has made great progress in tumor therapy, there is still a problem of low response rate in the treatment of many solid tumors.
The main causes of resistance to PD-1 antibody tumor immunotherapy are: 1, tumor tissue T lymphocyte infestion, so-called "cold tumor"; Tumor immunosuppressive micro-environments made up of immunosuppressive cells such as Treg weaken their anti-tumor immune response;3. Physiological barriers such as tumor malformed vascular structure, high interstitial hydraulics, and dense extracellular substations hinder the effective accumulation and deep penetration of PD-1 antibodies in tumor tissue.
many challenges in how to solve these problems to enhance the therapeutic effect of PD-1 antibody.
previous studies have shown that M2 tumor-related macrophages (TMs) play an important role in promoting tumor growth, angiogenesy, tumor metastasis and immune escape.
metfromin is widely used to treat diabetes because of its good blood sugar-lowering effects, few side effects and low cost.
In addition, numerous studies have shown that metformin can regulate tumor metabolism, block tumor cell cycles, inhibit angiogenesis, and kill cancer stem cells by activating 5'-monophosphate adenosine (AMP)-activated protein kinase (AMPK).
January 19, 2021, a team of Professors Yang Xiangliang, Professor Gan Wei and Huang Bo of the Chinese Academy of Medical Sciences published a research paper online in the journal Nature Communications entitled Boosting Anti-PD-1 Therapy with Metformin-Loaded Macrophage-Derived Microparticles.
team built macrophage-sourced microparticles (MPs) modified with glycerides (Man) and loaded metformin.
The drug-carrying microparticles (Met@Man-MPs) can effectively target tumor M2 tumor-related macrophages (TAM), promote M2 tumor-related macrophages (TAM) inverse polarization into anti-tumor activity M1 type, effectively inhibit tumor growth.
confirmed that Met@Man-MPs can effectively improve the therapeutic effect of PD-1 antibodies and form long-term anti-tumor immune memory in a variety of animal model anti-tumor experiments.
this study provides a new strategy for improving the therapeutic effect of PD-1 antibodies.
recent studies have shown that metformin effectively reverse-polarizes M2 tumor-related macrophages (TAMs) into M1 vertephages through ampK-NF-B signaling path paths, thereby inhibiting tumor growth and metastasis.
, however, there are still significant challenges in achieving the target delivery of metformin to M2 tumor-related macrophages (TAM) to further improve the effectiveness of cancer treatment.
's team used macrophages with natural tumor targeting and the high expression of glyceride-like macrophages (TAM) in M2 tumor-related macrophages (TAM), built a macrophage source microparticle (MPs) modified with glycerides (Man) and loaded metformin.
This drug-carrying microparticle (Met@Man-MPs) can effectively target tumor M2 tumor-related macrophages (TAM), promote M2 tumor-related macrophages (TAM) inverse polarization into anti-tumor activity M1 type, effectively inhibit tumor growth.
Met@Man-MPs can effectively improve the tumor immune micro-environment, using its inverse polarization into M1 tumor-related macrophages (TAM) secretion of cytokine TNF-α and other promotion of CD8-T cell recruitment, and reduce bone marrow source inhibitory cells (MDSC), regulatory T cells (Treg) more importantly, Met@Man-MPs carry a substation metal protease (MMPs) with macrophage sources that effectively degrade the tumor's extracellular substation, increase the deep immersion of CD8-T cells into tumor tissue, and PD-1 antibodies penetrate the rich and deep parts of tumor tissue.
confirmed that Met@Man-MPs can effectively improve the therapeutic effect of PD-1 antibodies and form long-term anti-tumor immune memory in a variety of animal model anti-tumor experiments.
this study provides a new strategy for improving the therapeutic effect of PD-1 antibodies.
Professor Yang Xiangliang, Professor Gan Wei and Professor Huang Bo of the Institute of Basic Medicine of the Chinese Academy of Medical Sciences are co-authors of the paper, and Wei Zhaoxuan and Zhang Xiaoqiong, Ph.D. students in the School of Life Sciences and Technology of Hua zhong University of Science and Technology, are co-authors of the paper.
Zhang Bixiang of Tongji Hospital, affiliated with Tongji Medical College of Huahua University of Science and Technology, Dr. Yu Jingjing and Dr. Huang Gang of Hua zhong University of Science and Technology were involved in the work.
this work has been the national key research and development program and the National Natural Science Foundation and other projects funded.