Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy

Abstract

Highlights aCD3/F/AN, anti-CD3e f(ab′)2 fragment-modified and fenofibrate-encapsulated amphiphilic nanoparticle, reprogrammed mitochondrial lipid metabolism of T cells. aCD3/F/AN specifically activated T cells in glucose-deficient conditions mimicking tumor microenvironment, and exerted an effector killing effect against tumor cells. In vivo treatment with aCD3/F/AN increased T cell infiltration, cytokine production, and prevented tumor growth. Abstract We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming. Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles (F/ANs), and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment, yielding aCD3/F/ANs. An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs. aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae, a higher membrane potential, and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations. Peroxisome proliferator-activated receptor-α and downstream fatty acid metabolism-related genes are expressed to a greater extent in aCD3/F/AN-treated T cells. Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment. Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells. In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues. The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth. Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer

“…The researchers found that aCD3/F/ANs can promote the proliferation of T cells in the TME with low glucose level by enhancing fatty acid metabolism, and enhance its anti-tumor effect. Anti-cd3e F (AB’)2 fragment modification of fenofibrate-coated amphiphilic nanoparticles can reprogram the mitochondrial lipid metabolism of T cells to make use of different energy substrates, which may be a feasible strategy to improve immunotherapy [ 177 ].…”

Lipid Metabolism Regulation Based on Nanotechnology for Enhancement of Tumor Immunity

“…To improve the functions of CD8 + T cells in the TME, Dongyoon et al designed a targeted nanoparticulate system that can activate the anticancer activity of T cells through lipid metabolic regulation ( Kim D. et al, 2021 ). The amphiphilic polyglutamic acid nanoparticles encapsulated fenofibrate (PPARα agonist) and the anti-CD3e f (ab′)2 fragment was modified on the nanoparticle surface to obtain the anti-CD3e-modified, fenofibrate-encapsulated nanoparticles (termed aCD3/F/ANs) ( Kim D. et al, 2021 ). The aCD3/F/ANs efficiently targeted T cells by binding with CD3 receptor ( Figure 2A ), which is a marker of mature T cells preserved in various tumors.…”

“… aCD3/F/AN mediated lipid metabolic reprogramming in T cells for immune-metabolic therapy ( Kim D. et al, 2021 ). (A) Preparation of aCD3/F/AN nanoparticles.…”

“…The fast-cycling tumor cells rely on aerobic glycolysis for energy supply, while the slow-proliferation cancer cells under glucose-deprived conditions use lipid oxidation as the main metabolism pattern ( Hoang-Minh et al, 2018 ). Nanotechnology, which is emerging as a promising therapeutic tool for targeting some specific tissues or cells, has been actively explored for application in anticancer immunity enhancement via regulating metabolism, e.g., glycolysis ( Wang et al, 2019 ; Chen et al, 2020 ) and lipids ( Jin et al, 2019 ; Kim D. et al, 2021 ). Therefore, nanotechnology-based targeting delivery may provide a potential method for cell-targeting regulation of lipid metabolism in the TME for improving immunotherapy.…”

Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors

“…In lung adenocarcinoma tissues, the upregulation of miR-130b also promoted cell metastasis and invasion (Kim et al. 2021 ).…”