Epigenetic regulators combined with tumour immunotherapy: current status and perspectives

Abstract

Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.

Keywords: DNA methyltransferase inhibitor; Epigenetic regulation; Histone deacetylase inhibitors; Immune check inhibitor; Tumour immunotherapy.

Fig. 1

Advantages of cancer treatment strategies employing epigenetic regulators in conjunction with tumour immunotherapy. Tumour immunotherapy has shown strong therapeutic advantages and therapeutic potential in tumour treatment, and the treatment of tumour patients is developing well, but there are still some adverse events related to immunotherapy, such as myocarditis, liver function damage, rash, renal function damage, lung injury, and even life-threatening in severe cases. Epigenetic regulatory factors show therapeutic potential in tumours and other diseases. The purpose of this review is to discuss the research effect, clinical application potential and problems of tumour immunotherapy, such as immune checkpoint inhibitor drugs such as pabolizumab, karelizumab, duvalizumab and epigenetic regulators such as romidixin and decitabine, in the treatment of various types of tumours

Fig. 2

Influence and function of immune cells on carcinogenesis and tumour metastasis. Immune cells in the body participate in innate and adaptive immune responses in the process of tumour occurrence, respectively. In different types of immune responses, immune cells interact with each other through secretion factors and other mechanisms. These effects have both positive and negative effects on tumour occurrence, development and tumour metastasis

Fig. 3

Types of tumour immunotherapy. Tumour immunotherapy can be divided into cytokine therapy, immune vaccine, immune checkpoint blocking and adoptive cell transplantation. Cytokines mainly include TGF-β, IFN γ, TNF-α, IL-4, IL-5, IL-9 and so on. Immune vaccines are divided into whole-cell vaccine, DNA vaccine, mRNA vaccine and DC cell vaccine. The commonly used inhibitors of ICB are PD-1, PD-L1 and CTLA-4 inhibitors. CAR-T therapy is often used in adoptive cell transplantation therapy

Fig. 4

The dual role of immunotherapy. Tumour immunotherapy plays an anti-tumour role mainly through the immune function of immune cells in the body. Immune cells in the body can be roughly divided into two categories, namely, fall-inhibitory cells and fall-supportive cells, and each immune cell plays a corresponding role mainly by secreting different factors

Fig. 5

Mechanism of epigenetic regulator on immunity. Epigenetic therapy and immunotherapy have a synergistic effect, which is mainly mediated by the de-repression of the promoter encoded by ERVs. Epigenetic regulators upregulate MHC, co-stimulatory molecules and tumour-associated antigens, and immune checkpoints CTLA4, PD1 and PD-L1 induce the increase of cytokine secretion and inhibit MDSCs, remodelling tumour immune microenvironment