Tumor-associated macrophages (TAMs) play a pivotal role in regulating tumor development and are meaningful therapeutic targets. Professor Shen Pingping’s team has long been engaged in the study of TAMs’ functions and regulatory mechanisms, and has developed immunotherapy techniques based on clinical practice. Significant research progress has been made in the reprogramming of macrophage metabolism and the construction of new immunotherapy strategies based on it. Recently, another study found that the rate-limiting enzyme of gluconeogenesis, pyruvate carboxylase (PCB), plays a non-classical biological function and changes the polarization phenotype of TAMs to mediate tumor progression.
PCB is one of the rate-limiting enzymes in the gluconeogenesis pathway and plays a key role in converting non-sugar substances to sugar, maintaining cellular energy homeostasis. However, the discovery of non-classical biological functions of PCB is rare. When analyzing human tumor tissue samples, researchers found a significant difference in PCB abundance between TAMs and normal tissue macrophages. In-depth analysis based on this showed that hypoxia in tumor tissue is a key factor inducing a decrease in PCB abundance and activity in TAMs, and the downregulation of PCB levels in TAMs is closely related to immune escape and tumor progression. The mechanism by which PCB acts is by reshaping the macrophage skeleton through promoting the binding of myosin MYH6 to F-actin, driving TAMs to phagocytose tumor cells. Inspired by these results, researchers further constructed a dual-functional nanoparticle FDC-GTA@HSA for oxygen delivery/PCB activation. By simultaneously improving hypoxia and activating PCB, FDC-GTA@HSA inhibiting the IRF1-PD-L1 axis, and reprogramming the tumor-killing ability of TAMs. FDC-GTA@HSA also enhanced the infiltration of CD8+ T cells in the microenvironment and reversed the immunosuppressive state of the microenvironment (Figure 1). This study not only discovered the non-classical biological function and novel regulatory mechanism of PCB but also constructed a patented technology for targeted intervention of TAMs polarization, which can be used to further construct new immunotherapy strategies.
The research titled Intervening pyruvate carboxylase stunts tumor growth by strengthening anti-tumor actions of tumor-associated macrophages was published in Signal Transduction and Targeted Therapy (STTT) in February 2022, with the paper link at https://www.nature.com/articles/s41392-021-00807-w. PhD students Shu Yuxin, Yang Nanfei, and Cheng Nan were mainly responsible for the experimental research in this work, with Dr. Zou Zhengyun, chief physician of the Tumor Research Center of Nanjing Drum Tower Hospital affiliated to Nanjing University, and Dr. Shi Qian from the University of Texas Health Science Center also participating in the research work.
Professor Shen Pingping (Nanjing University) and Professor Zhu Wei-Guo (Shenzhen University) were co-corresponding authors of the paper. This research was supported by the National Key Research and Development Plan (2017YFA0506000), the Key Research and Development Program of Jiangsu Province-Social Development Projects (BE2020687) and the National Natural Science Foundation of China (81673439, 82073365).
Figure 1. Targeting PCB to reprogram TAM’s immune killing function.
https://www.nature.com/articles/s41392-021-00807-w