Lipocalin-2+ Mast Cells in Lymph Nodes Promote Tumor Progression via a Mitochondrial-derived Peptide

Mast cells (MCs) play a pivotal role in barrier tissues that connect to the external environment, but their distribution and functions in lymph nodes (LNs) remain largely unclear, especially during the tumor progression. Here, using single-cell RNA sequencing (scRNA-seq), photoconversion tumor cell lines, MC-deficient KitW-sh mice and lipocalin-2-deficient mice, we show that MCs in LNs promote the stemness of tumor cells metastasizing to LNs and their further dissemination to distant organs. Mechanistically, lipocalin-2, which is secreted by LN MCs, facilitates the generation of mitochondrial peptide MOTS-c by opening the mitochondrial permeability transition pore (mPTP), which promotes the activity of the stem cell transcription factor TFCP2L1. Aptamers of MOTS-c or lipocalin-2 neutralization inhibit the MC-mediated stemness of tumor cells and reduce lung metastasis. Overall, we reveal the function of LN MCs and identified an appealing therapeutic strategy for tumor metastasis.