The dual roles of lysine-specific demethylase 1 (KDM1A/LSD1) in the modulation of tumor immune microenvironment and its inhibitors in colorectal cancer.

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated significant potential in cancer therapy. However, the immunosuppressive nature of the tumor microenvironment (TME) and ICI remains a major challenge in clinical treatment. Recently, epigenetic regulators, such as the histone demethylase Lysine (K)-Specific Demethylase 1 A(KDM1A/LSD1), have participated in tumor progression and immune evasion by reshaping the epigenetic state of tumor cells and the immune microenvironment. This study systematically reviewed the dual role of KDM1A in colorectal cancer (CRC). On one hand, KDM1A can promote tumor cell proliferation and aberrant differentiation by regulating signaling pathways, such as Wnt/β-catenin and Notch. On the other hand, it can also modulate the functions of T cells, B cells, macrophages, and Natural Killer (NK)cells through epigenetic modifications, thus inhibiting antitumor immune responses and creating an immunosuppressive microenvironment. Notably, KDM1A can reduce the immunogenicity of CRC by downregulating tumor antigen presentation or pro-inflammatory cytokine secretion, thus enhancing the tumor's resistance to ICI. Clinically, small-molecule inhibitors targeting KDM1A, such as Tranylcypromine (TCP) and Iadademstat, could enhance the efficacy of ICIs by reversing the immunosuppressive microenvironment, especially in mismatch repair proficient (pMMR) CRC. Future studies should further elucidate the molecular networks of KDM1A regulating immunogenicity and explore the synergistic mechanisms of its inhibitors with other epigenetic drugs or immunotherapies in order to provide new strategies for overcoming CRC resistance to immunotherapies.