Lysine methylation modifications in tumor immunomodulation and immunotherapy: regulatory mechanisms and perspectives

Abstract

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.

Keywords: Cancer immunotherapy; Epigenetic; Immunomodulation; Lysine demethylases (KDMs); Lysine methylation; Lysine methyltransferases (KMTs).

Fig. 1

Overview of lysine methylation. (A) The processes of lysine methylation and demethylation are depicted. Lysine methyltransferases (KMTs) catalyze the addition of methyl groups onto substrates, while lysine demethylases (KDMs) remove methyl groups, resulting in mono-, di-, and trimethylation of lysine residues. (B) Typical lysine methylation sites on core histone proteins H3 and H4 are illustrated

Fig. 2

Mechanisms of lysine methylation modifications regulating immune cells. Lysine methyltransferases and demethylases in immune cells modulate important signaling pathways and molecular expression through histone or non-histone methylation, influencing proliferation, differentiation, apoptosis, and activation of lymphoid and myeloid cells

Fig. 3

Impact of lysine methylation modifications on immune evasion. Lysine methylation modifications play indispensable roles in regulating immune evasion in various tumors. They affect antigen presentation by influencing MHC class I molecule expression, alter T cell function through modulation of T cell chemoattractant, and influence immune checkpoint regulation

Fig. 4

Effects of lysine methylation modifications on CAR-T cell therapy. Enhancing the proliferation capacity and anti-tumor activity of CAR-T cells through genetic editing or targeting the lysine methylation levels of tumor cells with small molecule drugs both contribute to improving the efficacy of CAR-T cell therapy