Synergistic Effect of Repolarization of M2 to M1 Macrophages Induced by Iron Oxide Nanoparticles Combined with Lactate Oxidase

Zi-Xian Liao,Da-Liang Ou,Chia-Chen Hsieh,Ming-Jung Hsieh

doi:10.3390/ijms222413346

Abstract

Metabolic reprogramming of tumors with the accompanying reprogramming of glucose metabolism and production of lactate accumulation is required for the subsequent development of tumors. Recent evidence has indicated that tumor-secreted lactate can promote an oncolytic immune microenvironment within the tumor. Furthermore, tumor-secreted lactate directly induces polarization of tumor-supportive M2 macrophages. However, oxidized tumor-secreted lactate in the tumor microenvironment can be exploited. Iron oxide nanoparticles have shown promising anticancer potential by activating tumor-suppressing macrophages. Furthermore, lactate oxidase (LOX) generally oxidizes tumor-secreted lactate and subsequently converts to pyruvate. Particularly, the ratio of M2 macrophages to M1 macrophages corresponds with tumor growth. In this study, we present iron oxide nanoparticles with carboxylic acid combined with LOX that enhance antitumor efficacy as a synergistic effect on the repolarization of tumor-supportive M2 macrophages to tumor-suppressive M1 macrophages in a tumor microenvironment. After M2 macrophages treated with iron oxide nanoparticles were combined with LOX, the ratio of M1 macrophages was significantly greater than iron oxide nanoparticles alone or with LOX alone. It is concluded that the inhibition of cancer cell proliferation by ratio of M1 macrophages was observed. This study suggests that the iron oxide nanoparticles combined with LOX could be potentially used for potentiating immune checkpoint inhibitor therapies for cancer treatment.

Highlights

Macrophages Incubated with Iron Oxide Nanoparticles Combined with Lactate oxidase (LOX)
We evaluated whether M2 macrophages can be repolarized to M1 macrophages when M2 macrophages exposed to LOX alone, iron oxide nanoparticles, or iron oxide nanoparticles combined with LOX at a single dose or triple doses under an acidic pH after 3 days of incubation
F4/80+ inducible nitric oxide synthase (iNOS)− CD206+ s for M2 macrophages (Figure 6) and consistent with the flow cytometric analysis (Figure 5a–c). These results reveal that lactate oxidizes into pyruvate by using LOX, decreasing the maintained M2 macrophages, and cellular uptake of iron oxide nanoparticles at the optimized particle size of 5 nm improves the repolarization of M2 to M1 macrophages

Summary

Introduction

The US Food and Drug Administration (FDA) has approved immune checkpoint inhibitors (ICIs), which show promise in changing the landscape of drug development for cancer therapy [1,2,3]. Tumor or cancer cells derive constituents to promote macrophages to a tumorpromoting status from a tumor-killing status. Immunotherapeutic approaches enhance Tcell-mediated immune responses and allow for control over polarization and recruitment of macrophages, especially to inhibit cancer progression [6,7]. Recent evidence has indicated that tumor-secreted lactate can promote an oncolytic immune microenvironment within the tumor [3,8]. The tumor microenvironment typically consists of dynamically produced growth factors, cytokines, and metabolic product such as lactate. PH changes associated with lactate affect the immune system and tumor growth [3,8,10,11].

Results

Discussion

Conclusion