Authors
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
Published in
Cancer research. Sep 15, 2026. Epub Sep 15, 2026.
Abstract
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.
PMID:
42743229
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 27
- Comments 0