Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.
12 affiliations
- 1Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.
- 2Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 3Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
- 4Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 5Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 6Spectral Flow Unit, Fondazione Istituto Nazionale Di Genetica Molecolare-INGM, Milan, Italy.
- 7Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 8Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 9Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
- 10Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
- 11Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy. [email protected].
- 12Division of General Surgery, University Maggiore Hospital Della Carità, Novara, Italy. [email protected].
Abstract
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.
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BibTeX
@article{civeslosada2026lysinespecific,
title = {{Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.}},
author = {Candela Cives-Losada and Cristiana Soldani and Michela Anna Polidoro and Barbara Franceschini and Flavio Milana and Aurora Gazzillo and Antonella Cammarota and Chiara Camisaschi and Francesca Clemente and Achille Anselmo and Luca Di Tommaso and Guido Torzilli and Domenico Mavilio and Ana Lleo and Matteo Donadon},
journal = {Molecular biomedicine},
year = {2026},
month = oct,
doi = {10.1186/s43556-026-00602-5},
url = {https://europepmc.org/article/MED/42900293},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.
AU - Candela Cives-Losada
AU - Cristiana Soldani
AU - Michela Anna Polidoro
AU - Barbara Franceschini
AU - Flavio Milana
AU - Aurora Gazzillo
AU - Antonella Cammarota
AU - Chiara Camisaschi
AU - Francesca Clemente
AU - Achille Anselmo
AU - Luca Di Tommaso
AU - Guido Torzilli
AU - Domenico Mavilio
AU - Ana Lleo
AU - Matteo Donadon
PY - 2026
DA - 2026/10/20
JO - Molecular biomedicine
DO - 10.1186/s43556-026-00602-5
UR - https://europepmc.org/article/MED/42900293
AB - 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.
SN - 2662-8651
ER -