Yue Liu, Im-Meng Sun, Marc Creixell, Jordan Brown, Samir Kharbanda, James J Lee, Varahram Shahryari, Kayley Hake, Jacqueline O'Hara, Kenneth J Finn, Nianxin Yang, Lolita Penland, Jiaxi Wang, Ka Man Li, John Balibalos, Aaron W Stebbins, Patrick M Godfrey, Po-Han Tai, Evangelia Malahias, Wenjun Kong, Nicole Fong, David Hendrickson, Shagun Gupta, Leanne Jg Chan, Fiona E McAllister, Chirag H Patel, Marcia N Paddock, Tuan Andrew Nguyen, Fiona A Harding, Jonathan D Powell
Metastasis remains the leading cause of cancer mortality, yet effective therapies for inhibiting and treating metastasis are limited. Therapeutic responses are influenced by organ-specific immune microenvironments, highlighting the need to develop strategies to pharmacologically modulate these niches. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrated that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell and spatial transcriptomics and functional assays revealed that AC484 promotes accumulation, IFNγ production and responsiveness, and tumor-killing activity of AMs within metastatic lesions. Depletion of AMs diminished the anti-metastatic efficacy of AC484. Mechanistically, inhibition of PTPN1/2 amplified IFNγ-STAT1 signaling in AMs, and disrupting this pathway impaired the tumor control capability of AC484. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient.