Abstract Background: Brain metastasis (BM) is a leading cause of death in lung cancer patients, and the brain’s unique microenvironment is key to metastatic initiation and progression. However, the molecular mechanisms of tumor microenvironment crosstalk in lung cancer BM remain unclear. Lipocalin-2 (LCN2) is associated with inflammation and cancer, but its specific role in lung cancer BM is undefined. Methods: Single-cell sequencing analysis was conducted on BM specimens from patients with lung cancer BM, and data mining of public databases was performed to identify key molecules. Cell lines with stable LCN2 knockdown or overexpression were constructed using lentiviral transduction. Transcriptome sequencing and immunofluorescence assays were applied to verify the in vitro functions of LCN2, including its regulatory effects on downstream signaling pathways and cellular behaviors. For in vivo studies, murine models of lung cancer BM were established via brain orthotopic injection and intracardiac injection of tumor cells. Bioluminescence imaging and multiplex immunofluorescence staining was utilized to investigate the role of LCN2 in BM tumor initiation and progression, as well as its interaction with brain microenvironmental components. Results: LCN2 was upregulated in BM compared to primary tumors, correlating with shorter intracranial disease-free and overall survival and plasma LCN2 was higher in BM patients. LCN2 is dispensable for BBB transmigration but is essential for promoting tumor growth within the brain microenvironment. LCN2 promoted intracranial tumor growth and upregulates VEGF-A via the JAK2/STAT3 signaling pathway to facilitate angiogenesis in lung cancer BM. More importantly, LCN2 bound to SLC22A17 on astrocytes to activate the JAK2/STAT3 signaling pathway and induce CCL2 secretion, which recruited macrophages that secreted IL-1β to upregulate LCN2 in tumor cells via the IL-1R-NF-κB signaling axis. Inhibition of IL-1β-IL-1R and JAK2/STAT3 signaling by IL-1R inhibitor anakinra combined with STAT3 inhibitor SH4-54 an suppress LCN2-driven tumor progression. Conclusions: Tumor-derived LCN2 orchestrates a brain-specific metastatic program through dual mechanisms: a paracrine loop involving astrocyte activation and macrophage recruitment and a tumor-intrinsic angiogenic pathway via SLC22A17-JAK2-STAT3-VEGF-A signaling. These mechanistic insights suggest that LCN2 may serve as both a therapeutic target and a prognostic biomarker in lung cancer BM. Citation Format: Danming He, Yixiang Zhu, Jian Zhang, Wei Zhuang, Hua Bai, Jie Wang. Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4093.
He et al. (2026) studied this question.