Pharmacological inhibition of LSD1 suppresses the CD155/TIGIT immune checkpoint axis and enhances NK cell-mediated cytotoxicity in colorectal cancer.

Abstract

Colorectal cancer (CRC) remains poorly responsive to immune checkpoint blockade in a substantial proportion of patients, highlighting the need to identify druggable mechanisms that regulate tumor immune evasion. CD155, a ligand of the inhibitory receptor TIGIT, is highly expressed in CRC and contributes to impaired natural killer (NK) cell-mediated antitumor immunity. Lysine-specific demethylase 1 (LSD1/KDM1A) is a pharmacologically targetable epigenetic enzyme with emerging roles in tumor immunogenicity, but whether LSD1 inhibition modulates the CD155/TIGIT immune checkpoint axis in CRC remains unclear. In this study, we found that LSD1 and CD155 were highly expressed in CRC tissues and showed a significant positive correlation. Genetic depletion of LSD1 reduced CD155 expression at both the mRNA and protein levels in CRC cells. Importantly, pharmacological inhibition of LSD1 with two small-molecule inhibitors, CC-90011 and ORY-1001, markedly decreased CD155 expression and membrane abundance in multiple CRC cell lines. Mechanistically, LSD1 depletion or inhibition increased H3K4me2 enrichment at the CD155 promoter, suggesting that LSD1 activity is required for maintaining CD155 transcription in CRC cells. Functionally, LSD1 inhibition decreased CD155 expression and cell-surface abundance, resulting in reduced CD155/TIGIT interaction and enhanced NK cell-mediated cytotoxicity, accompanied by increased secretion of IFN-γ and TNF-α. In a CT26 syngeneic tumor model, LSD1 knockdown suppressed tumor growth and decreased CD155 expression in vivo. Collectively, these findings reveal that pharmacological inhibition of LSD1 attenuates CRC immune escape, at least in part, by epigenetically suppressing the CD155/TIGIT axis. This study provides a rationale for exploiting LSD1 inhibitors as immunomodulatory agents to enhance antitumor immunity in CRC.