Single-cell analysis reveals IL1B⁺ macrophages promote lung metastasis in adenoid cystic carcinoma

A high rate of metastasis remains a challenge for the treatment of adenoid cystic carcinoma (ACC), yet the underlying mechanism of lung metastasis remains elusive. By integrating single-cell RNA sequencing and bulk transcriptomics with multiplex immunohistochemistry, we identified a metastatic niche consisting of IL1B⁺ tumor-associated macrophages (TAMs), CD24⁺ luminal-like tumor cells, ACKR1⁺ endothelial cells (ECs) and HSPA1A⁺CD8⁺ T cells. Importantly, we revealed that IL1B⁺ TAMs play diverse roles in the processes of tumor cell intravasation and colonization, two fundamental steps supporting metastatic outgrowth. In primary lesions, IL1B⁺ TAMs release elevated levels of VEGFA and MMPs, thereby coupling sprouting angiogenesis with extracellular matrix remodeling to facilitate cancer cell intravasation. In metastatic lesions, IL1B⁺ TAMs bind to IL-1R1 on ACKR1⁺ ECs to upregulate the expression of the adhesion molecule SELP, which can attract CD24⁺ luminal-like tumor cells for lung colonization. IL1B⁺ TAMs also increase the stress response state of HSPA1A⁺CD8⁺ T-cell recruitment and induce T-cell exhaustion, thereby facilitating the survival of disseminated tumor cells. Mechanistically, MIF derived from CD24⁺ tumor cells increases the transcription of IL1B in TAMs. We also reported that the infiltration of IL1B⁺ TAMs increased steadily with increasing lung metastatic progression in mice bearing metastatic ACC cells. Elevated plasma IL-1β and VEGFA levels are associated with increased metastatic burden and poor overall survival in patients with ACC. Our findings reveal the critical role of IL1B⁺ TAMs in reshaping the metastatic tumor immune microenvironment and reveal a potential therapeutic vulnerability for metastatic ACC.