Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases

Colorectal liver metastases (CRLM) are a major cause of mortality in colorectal cancer and are characterised by a profoundly immunosuppressive tumour microenvironment in which tumour-associated macrophages (TAMs) play a central role. However, the molecular mechanisms driving TAM plasticity and maintenance remain poorly understood. Here, we investigated macrophage heterogeneity in CRLM and examined the contribution of the epigenetic regulator lysine-specific demethylase 1 (LSD1) to TAM polarisation. Analysis of patient-derived specimens by flow cytometry, immunohistochemistry and transcriptional profiling identified a population of large TAMs (L-TAMs) enriched in the peritumoral niche that displayed an immunosuppressive, M2-like phenotype and was associated with poor clinical outcome. In contrast, smaller TAMs (S-TAMs) exhibited a more inflammatory transcriptional programme, including increased IL1β expression. Tumour-conditioned media reproduced these distinct macrophage phenotypes in vitro, indicating that tumour-derived factors actively shape TAM identity. Pharmacological inhibition of LSD1 using baicalin or INCB059872 reduced the expression of CD206 and the immune checkpoint molecule PD-L1, consistent with macrophage reprogramming away from a tumour-promoting state. Collectively, these findings identify LSD1 as an epigenetic regulator of macrophage plasticity in CRLM, implicated in the maintenance of immunosuppressive TAM phenotypes, and potentially able to induce phenotypic reversion. Our findings identify LSD1 as a regulator of TAM phenotype and support further investigation of LSD1 targeting as a strategy to remodel the metastatic tumour microenvironment and potentially enhance anti-tumour immunity.