Tumor-derived amyloid-β drives TREM2⁺ macrophages immunosuppression in cholangiocarcinoma

Cholangiocarcinoma (CCA) is an aggressive malignancy with limited therapeutic options. In this study, we explored the role of TREM2⁺ tumor-associated macrophages (TAMs) in modulating the immune microenvironment and their impact on anti-PD-1 therapy. Using single-cell RNA sequencing data and immunohistochemical analysis, we identified a significant upregulation of TREM2 in TAMs in human CCA, correlating with decreased CD8⁺ T cell infiltration and poor prognosis. TREM2 deficiency in a mouse model of CCA led to a reprogramming of TAMs to a pro-inflammatory phenotype, with a marked increase in CD86⁺ macrophages and a significant reduction in CD206⁺ macrophages. This phenotypic shift enhanced the recruitment and activity of CD8⁺ T cells, driving a potent pro-inflammatory immune response. Additionally, we uncovered that Aβ produced by CCA cells contributes to TAM polarization through TREM2/PI3K/AKT1 signaling pathway. Blocking Aβ signaling further augmented TAM reprogramming and CD8⁺ T cell infiltration. The combination of TREM2 deletion and Aβ inhibition significantly enhanced the efficacy of anti-PD-1 therapy, resulting in reduced tumor growth, increased survival, and improved overall therapeutic outcomes in both subcutaneous and hydrodynamic tail vein CCA models. These findings suggest that targeting TREM2 and Aβ in conjunction with anti-PD-1 immunotherapy holds promise as a novel therapeutic strategy for CCA.