Repolarization of M2 to M1 Macrophages Triggered by Lactate Oxidase Released from Methylcellulose Hydrogel

Abstract

Deregulated proliferation of tumors is generally associated with altered energy metabolism. A high rate of anaerobic glycolysis in solid tumors contributes to an acidification of pH to ∼6.7–7.2 in the tumor microenvironment and lactate accumulation. Macrophages in the tumor microenvironment can be educated by tumor cells. Tumor-derived lactate induces the polarization of M2 macrophages and promotes tumor invasion and metastasis. However, a particular challenge is to sustain lactate depletion. We propose that the repolarization of the tumor-supportive M2 macrophage to the tumor-suppressive M1 macrophage after the depletion of lactate by lactate oxidase (LOX) released from the hydrogels in the tumor microenvironment may enhance the antitumor treatment efficacy.

Going ballistic: Leishmania nuclear subversion of host cell plasticity

“…Likewise, Leishmania-infected macrophages seem to express a mixed profile and may define a new polarization state that remains to be investigated in detail [70]. These macrophage phenotypes are transient and reversible [71][72][73] and thus can be exploited for treatment, as illustrated by current efforts to target TAMs for cancer treatment [74].…”

Characterization of tumor‐associated macrophages in prostate cancer transgenic mouse models

“…[4][5][6] Given the plasticity of macrophages and their ability to repolarize, macrophages often do not fit neatly into these subtypes making classification of TAMs based on canonical subtypes complicated and imperfect. 4,5,[7][8][9][10] To date, the field has relied on an M1-M2 dichotomy spectrum to associate macrophage characteristics with either antitumor (M1) or pro-tumor (M2) functions. 8,11,12 While this has proved useful in providing a common language with which to describe TAMs, the field has advanced in its understanding of the nuances of TAM gene expression and behavior.…”

“…There are an array of subtypes that a macrophage can adopt which are categorized by the polarization stimuli, gene expression, and functional readouts (i.e., cytokine secretion, phagocytosis, and T cell activation) 4–6 . Given the plasticity of macrophages and their ability to repolarize, macrophages often do not fit neatly into these subtypes making classification of TAMs based on canonical subtypes complicated and imperfect 4,5,7–10 …”

Interferon Regulatory Factor 5 represses oxidative respiration in human and murine macrophages by inhibition of mitochondrial matrix protein GHITM

“…Some hallmarks of the IRF5-KO BMDM TCA cycle reproduce previous reports on TCA dynamics in the M2-like state. IRF5-KO BMDMs accumulate lactate in preference to pyruvate conversion at the end of glycolysis, this has been previously reported as characteristic of M2 macrophages in the tumour microenvironment [44][45][46][47] . In IRF5-KO BMDMs decreased pyruvate means it is less available as a substrate for mitochondrial metabolism.…”