Emerging Epigenetic-Based Nanotechnology for Cancer Therapy: Modulating the Tumor Microenvironment

Abstract

Dysregulated epigenetic modifications dynamically drive the abnormal transcription process to affect the tumor microenvironment; thus, promoting cancer progression, drug resistance, and metastasis. Nowadays, therapies targeting epigenetic dysregulation of tumor cells and immune cells in the tumor microenvironment appear to be promising adjuncts to other cancer therapies. However, the clinical results of combination therapies containing epigenetic agents are disappointing due to systemic toxicities and limited curative effects. Here, the role of epigenetic processes, including DNA methylation, post-translational modification of histones, and noncoding RNAs is discussed, followed by detailed descriptions of epigenetic regulation of the tumor microenvironment, as well as the application of epigenetic modulators in antitumor therapy, with an emphasis on the epigenetic-based advanced drug delivery system in targeting the tumor microenvironment.

Keywords: DNA methylation; cancer treatment; histone modification; nanotechnology; tumor microenvironment.

Scheme 1

Epigenetic modulator‐based nanotechnology can effectively transfer “cold” tumors into “hot” tumors by targeting tumor cells and APCs (e.g., macrophages and DCs); and then, improve antitumor therapy.

Figure 1

The mechanisms of DNA methylation and histone modification. The basic unit of chromatin is the nucleosome in which DNA is tightly wrapped around a histone octamer core (consisting of H2A, H2B, H3, and H4). DNA methylation: DNA methyl transferases (DNMTs) can transfer the methyl of the S‐adenosylmethionine (SAM) donor to DNA at position 5 in cytosine. In normal cells, CpG islands at tumor suppressor gene (TSG) promoters are usually unmethylated and are characteristic of active transcription genes; however, abnormal DNA hypermethylation is related to tumorigenesis and transcriptional inactivation. Histone acetylation: histone lysine acetyltransferases (KATs) catalyze the acetylation of histone; thus, promoting chromatin opening and active gene transcription, while histone deacetylases (HDACs) initiate the process of histone deacetylation, which is less accessible by forming a condensed state. Acetylation of lysine residues can be read by bromodomain‐containing protein (BRD) family. Histone lysine methylation: histone lysine methyltransferases (KMTs) methylate lysine residues, which can be erased by histone lysine demethylases (KDMs). Histone arginine methylation: three types of protein arginine methyltransferases (PRMTs) can catalyze histone arginine methylation. Several epigenetic drugs including DNMT inhibitor (DNMTi), HDAC inhibitor (HDACi), BRD inhibitor (BRDi), lysine‐specific demethylase inhibitor (LSDi), and PRMT inhibitor (PRMTi), which act on DNA methylation, histone deacetylation, histone demethylation, and histone arginine methylation, have been approved for clinical cancer treatment.

Figure 2

Epigenetic modulator‐based nanotechnology for regulating TME by targeting tumor cells and APCs (e.g., macrophages and DCs). Epigenetic agent‐based nanomedicine may target tumor cells or APCs (including macrophages and DCs) after systemic delivery with the aid of EPR effect‐mediated passive targeting or ligand‐mediated active targeting. Epigenetic drugs including DNMTi, HDACi, BRD4i, and LSD1i, directly target tumor cells for regulating apoptosis, proliferation, migration, and therapy resistance, as well as for tumor microenvironment (TME) remodeling by inducing DC maturation and T cell activation and infiltration. Moreover, epigenetic modulator‐based nanotechnology can facilitate tumor‐associated macrophage (TAM) polarization by targeting macrophages and induce DC maturation by targeting DCs.

Figure 3

Epigenetic agent‐containing combination therapies target tumor cells for regulating apoptosis, proliferation, migration, and therapy resistance. Specific delivery of nanomedicine can be achieved via various strategies, including cell‐mediated homologous targeting, receptor‐mediated endocytosis (e.g., CD44 and αvβ3 integrin receptors), and TAT‐mediated cell penetration (e.g, cell‐penetrating peptide derived from the transactivator of transcription of HIV‐1). After delivery to tumor tissue, epigenetic drugs and other antitumor drugs can be released from nanoplatforms in response to the TME (e.g., pH, GSH, and enzyme) to exert optimal synergetic effects. The combination of epigenetic therapy and other antitumor therapies (including chemotherapy, radiotherapy, molecularly targeted therapy, traditional Chinese medicine therapy, and PA imaging) shows remarkable efficiency in the treatment of solid tumors through multiple mechanisms. Ligand, HA and iRGD; PA, photoacoustic imaging; PD‐1, programmed cell death protein 1; PD‐L1, programmed cell death‐ligand 1; Receptor, CD44 and αvβ3 integrin receptors; TAT, cell‐penetrating peptide.

Figure 4

Epigenetic agent‐containing combination nanomedicines target tumor cells for tumor immune microenvironment modulation. Nanomedicine can actively accumulate in the tumor cells via cell‐mediated homologous targeting and nonhomologous targeting (e.g., T lymphocyte membrane) as well as receptor‐mediated endocytosis (e.g., CD44). Epigenetic drugs and other antitumor drugs released from nanomedicine respond to TME (e.g., pH, GSH, and photoactivation‐triggered release). Epigenetic monotherapies or synergy with other therapies (including chemotherapy, molecularly targeted therapy, PTT, and PDT) facilitate the cancer‐immunity cycle by promoting the release of TAA, antigen presentation, T cell activation, trafficking, and infiltration; thus, exerting tumor killing. More specifically, 1) the release of TAAs are initiated by pyroptosis and ICD, 2) the antigen presentation ability of DCs is facilitated through TLR‐9 activation and DC maturation, 3) the activation, trafficking, and infiltration of T cells are enhanced by inhibiting PD‐L1‐mediated immune tolerance and Trp metabolism as well as increasing tumor‐infiltrating lymphocytes, 4) tumor killing is achieved by CTL and IFN‐γ. CTL, cytotoxic T cell; ICD, immunogenic cell death; Kyn, kynurenine; Ligand, HA; Receptor, CD44; PDT, photodynamic therapy; PTT, photothermal therapy; TLR9, toll‐like receptor‐9; TAA, tumor‐associated antigen; and Trp, tryptophan.

Figure 5

Epigenetic agent‐containing combination nanomedicines regulate macrophage repolarization. Epigenetic agent‐containing combination nanomedicines can be actively transported into macrophages in the TME through leaky tumor vasculature and receptors on the surface of macrophages. The combination of epigenetic therapy and other antitumor therapies (e.g., molecularly targeted therapy and traditional Chinese medicine therapy) synergistically enhances antitumor immunity and effectively inhibits the progression of tumors by repolarizing TAM2 to TAM1.