Supramolecular nanotherapeutics enable metabolic reprogramming of tumor‐associated macrophages to inhibit tumor growth

Abstract

Tumor-associated macrophages (TAMs) exist in multiple phenotypes across the spectrum, defined by an M1 antitumorigenic phenotype and an M2 pro-tumorigenic phenotype on two ends of the spectrum. A largely immunosuppressive tumor-microenvironment aids the polarization of the infiltrating macrophages to a pro-tumorigenic M2 phenotype that promotes tumor progression and metastasis. Recent developments in macrophage immunotherapy have focused on strategies to re-educate TAMs from an M2 to M1 phenotype.Recent findings in the realm of immuno-metabolism have indicated that distinct metabolic signatures accompany macrophages based on their polarization states (M1-Glycolysis and M2-TCA cycle). These metabolites are important drivers of cellular signaling responsible for acquiring these polarization states, with evidence showing that metabolism is essential to facilitate the energy requirements of immune cells and regulate immune cell response. We hypothesized that TAMs could be reprogrammed metabolically by co-delivery of drugs using a supramolecular nanoparticle system that could effectively rewire macrophage metabolism by simultaneous inhibition of the TCA cycle and upregulation of the glycolytic metabolic pathway. TLR7/8 agonist and Fatty Acid Oxidation (FAO) inhibitor loaded metabolic supramolecular nanoparticles (MSNPs) were synthesized. In vitro assays showed macrophages treated with MSNPs were reprogrammed from an M2 phenotype to an M1 phenotype while significantly upregulating phagocytosis. When injected in 4T1 tumorbearing mice, MSNPs treatment reduced tumor growth progression more than other treatments. Hence, the delivery of TLR7/8 agonist combined with an FAO inhibitor can enhance antitumor efficacy through metabolic reprogramming of tumor-associated macrophages.

Fatty acid metabolism of immune cells: a new target of tumour immunotherapy

“…In vitro, the phenotype of macrophages changes from M2 to M1 after MSNP treatment, with enhanced phagocytosis. In vivo experiments of 4T1 cell line mice showed that MSNP injection delays tumour growth and enhances anti-tumour immunity [ 113 ]. In another group of experiments, siRNA loaded onto a nano-platform with reductive response characteristics was used to silence monoacylglycerol lipase (MGLL) and the key receptor regulating macrophage phenotype (endogenous cannabinoid receptor-2 CBMQ 2), inhibit production of free fatty acids in pancreatic cancer cells and induce TAM reprogramming to M1, increasing secretion of tumour-killing factors (TNF-α, IL-12), both of which exert anti-tumour effects [ 114 ].…”

Effects of glycolysis on the polarization and function of tumor‑associated macrophages (Review)

“…Research has indicated that a SnSe nanosystem modeled using LDH may achieve M1 macrophage activation and restore its anti-tumor function by altering the tumor microenvironment and reprogramming the metabolic mode of TAMs from OXPHOS to glycolysis (68). By contrast, a novel supramolecular nanotherapeutic reprograms TAMs from the M2 type to the M1 type by inhibiting the TCA cycle and upregulating glycolytic metabolism, while significantly affecting phagocytic function (69).…”

Glycolysis regulation in tumor‐associated macrophages: Its role in tumor development and cancer treatment

“…140 A supramolecular nanoparticle system combining a TLR7/8 agonist and FAO inhibitor has been shown to shift TAMs to a pro-inflammatory phenotype by increasing glycolysis. 141 There are also some limitations to target TAMs glycolysis.…”

“…Arsenic trioxide and cryptotanshinone have a synergistic therapeutic effect in treating HCC, aerobic glycolysis in tumor tissue was decreased but increases macrophage glycolysis by activating the AMPK pathway, shifting TAMs to the M1 phenotype 140 . A supramolecular nanoparticle system combining a TLR7/8 agonist and FAO inhibitor has been shown to shift TAMs to a pro‐inflammatory phenotype by increasing glycolysis 141 …”