Tumor-associated macrophages (TAMs) represent a critical component of the tumor microenvironment, exhibiting remarkable plasticity that allows them to polarize between anti-tumor M1 and pro-tumor M2 phenotypes. Recent research has unveiled the pivotal role of histone modifications in regulating this polarization process, opening new therapeutic avenues for cancer immunotherapy.
Histone Modifications Shape TAM Identity
TAMs demonstrate extraordinary phenotypic plasticity, with their functional state largely determined by epigenetic mechanisms. M1-type TAMs, characterized by strong antigen-presenting activity and secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, and TNF-α, exert anti-tumor effects through direct cytotoxicity and antibody-dependent cell-mediated mechanisms. Conversely, M2-type TAMs promote tumor progression through immunosuppression, angiogenesis facilitation, and tissue remodeling.
Histone modifications serve as master regulators of this polarization process. These epigenetic marks, including methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, crotonylation, and lactylation, dynamically alter chromatin structure and gene accessibility, thereby controlling TAM phenotype and function.
Methylation Drives M2 Polarization
Histone methyltransferases (HMTs) have emerged as key drivers of M2 polarization. Protein arginine methyltransferase 1 (PRMT1) positively regulates peroxisome proliferator-activated receptor γ (PPARγ) expression through H4R3me2a modification at the PPARγ promoter, promoting M2 polarization. The PRMT1/IL-6/STAT3 axis has been shown to enhance alcohol-associated hepatocellular carcinoma progression by inducing M2 polarization in mice.
ASH1L, an H3K4 methyltransferase, increases expression of Ccl2 and Csf1, which polarize M2-like pro-tumorigenic macrophages in hepatocellular carcinoma. Similarly, KMT2D enhances Ccl2 expression, promoting M2 polarization of TAMs in head and neck squamous carcinoma.
The histone methyltransferase complex component EZH2 catalyzes H3K27me3 and plays a crucial role in TAM regulation. EZH2-mediated H3K27me3 can inhibit Ccl2 expression in enhancer regions, reducing macrophage infiltration in small-cell lung cancer. Additionally, EZH2 can epigenetically silence Hif1α via H3K27me3 in promoter regions, with silenced TAMs manifesting inheritable M1 phenotype in melanoma.
Acetylation Balances M1 and M2 States
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) work in dynamic balance to regulate TAM polarization. HATs such as CREBBP and p300 promote M2 polarization by activating pathways including NOTCH/CCL2/CSF1 through H3K27 acetylation. The CTCF/PACERR complex can recruit p300, resulting in increased chromatin accessibility and transcriptional activation of PTGS2, a critical driver of M2 polarization in pancreatic ductal adenocarcinoma.
Conversely, HDACs demonstrate complex, context-specific roles. HDAC2 promotes M2-type TAMs through acetylation of histone H3 and transcription factor SP1. Myeloid cell-specific deletion of Hdac2 and pharmacologic inhibition of class I HDACs in murine lung cancer models induced switching from M2-type to M1-type TAMs. However, HDAC4 and HDAC11 appear to have negative effects on M2 polarization, suggesting that increasing their expression could serve as targets for tumor immunotherapy.
Lactylation Links Metabolism to Immunosuppression
Histone lactylation represents a novel modification directly linking tumor metabolism to TAM function. Lactate produced by tumor cells through the "Warburg effect" accumulates in the tumor microenvironment and induces lactylation of histone H3K18la sites upon transport into macrophages, thereby activating transcription and enhancing M2-like TAM activity.
This metabolic-epigenetic axis promotes immunosuppressive properties by enhancing expression of anti-inflammatory cytokines like IL-10 and TGF-β. Inhibition of glycolysis or lactate production in monocyte-derived macrophages impairs IL-10 expression and T cell suppression, while abrogated histone lactylation leads to accumulation of intratumoral T cells and tumor growth delay.
Therapeutic Targeting of Histone Modifications
The discovery of histone modifications as regulators of TAM polarization has opened new therapeutic avenues. Histone deacetylase inhibitors (HDACis) have shown significant potential in cancer immunotherapy by enhancing immune system recognition and attack of tumor cells. They promote T-cell infiltration into tumors and improve efficacy of immune checkpoint inhibitors such as PD-1/PD-L1 antibodies.
Selective HDAC inhibitors targeting specific isoforms offer improved therapeutic windows and reduced side effects compared to pan-HDAC inhibitors. Several HDAC inhibitors, including vorinostat and romidepsin, have received FDA approval for treating cancers like cutaneous T-cell lymphoma.
Histone methyltransferase inhibitors (HMTis) also demonstrate promise in combination with immune checkpoint inhibitors. The EZH2 inhibitor EPZ-6438 enhances PD-L1 expression and protein stability, and combination with anti-PD-1 therapy improves the tumor microenvironment and enhances immunotherapy sensitivity.
Metabolic Reprogramming and Epigenetic Crosstalk
The interplay between metabolism and histone modifications in TAMs represents a critical regulatory mechanism. M1-type TAMs primarily rely on glycolysis for energy supply, while M2-type TAMs depend on oxidative phosphorylation from fatty acid oxidation. These metabolic changes directly influence histone modifications by altering availability of metabolites that serve as cofactors or substrates for epigenetic enzymes.
α-Ketoglutarate and succinate regulate activity of histone demethylases, while S-adenosylmethionine serves as the primary methyl donor for HMTs. Altered levels of these metabolites can affect histone methylation and gene expression in TAMs. The accumulation of lactate in the tumor microenvironment establishes an acidic environment that promotes histone lactylation and M2 polarization.
Clinical Implications and Future Directions
Current therapeutic approaches targeting TAMs focus on multiple strategies: inhibiting monocyte recruitment, selectively eliminating immunosuppressive M2 macrophages, reprogramming TAMs into anti-tumor phenotypes, and enhancing macrophage-mediated tumor growth inhibition. The complexity of histone modification crosstalk and dynamic plasticity of TAMs in the tumor microenvironment present both opportunities and challenges for therapeutic targeting.
Tumor heterogeneity and diversity of TAM subsets necessitate tailored strategies for different cancer types. Off-target effects and toxicity associated with broad-spectrum epigenetic inhibitors remain significant hurdles, underscoring the need for isoform-specific inhibitors or targeted delivery systems.
Future research should prioritize understanding TAM heterogeneity and regulatory mechanisms, developing more precise targeting strategies, and optimizing combination therapies. The integration of epigenetic, metabolic, and immunotherapeutic strategies offers a promising path forward for reshaping the tumor microenvironment, enhancing anti-tumor immunity, and improving outcomes for cancer patients.
