MARCO promotes cholangiocarcinogenesis by inducing immunosuppression and its targeting reduces tumor growth

Abstract Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary malignant tumors with poor prognosis and limited therapeutic options. Recent studies have highlighted the role of the immune system in the development and progression of intrahepatic CCA (iCCA). In this study, we investigated the role of the scavenger receptor MARCO in iCCA. Employing transcriptomic, spatial proteomic and histological analyses of human samples, MARCO was found on a specific subtype of tumor-associated macrophages linked to immunosuppression and extracellular matrix remodeling within the tumor microenvironment. High MARCO expression in human iCCA tumors correlated with worse overall survival, T cell dysfunction and increased collagen deposition. In line with this, MARCO expression was associated with a TH2-skewed immune response and was increased in macrophages exposed to IL-4 and IL-13. Marco −/− mice were protected against iCCA development, exhibiting reduced tumor burden, fewer innate immune cells related to TH2 responses and attenuated fibrosis. Moreover, Marco −/− mice exhibited lower levels of immunosuppressive markers on macrophages and cytotoxic T cells, resulting in improved overall survival and reduced lung metastases in an orthotopic tumor model. The use of an anti-MARCO antibody further reduced tumor volume in wild-type mice. This study identifies MARCO as a key regulator of immunosuppression, fibrosis and tumor progression in iCCA, and supports its potential as a novel therapeutic target for macrophage-directed immunotherapy.