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.