PTPN1/2 Inhibition Remodels the Pulmonary Myeloid Landscape to Induce Alveolar Macrophage-Mediated Control of Lung Metastasis

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Publication Details

Journal
Cancer Research
Published
2026-09-15
DOI
https://doi.org/10.1158/0008-5472.can-26-0770
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
0.00
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article

PTPN1/2 Inhibition Remodels the Pulmonary Myeloid Landscape to Induce Alveolar Macrophage-Mediated Control of Lung Metastasis

Nianxin Yang, Nicole Fong, David G. Hendrickson, John Balibalos et al.
Cancer Research
Protein Tyrosine Phosphatases
article

PTPN1/2 Inhibition Remodels the Pulmonary Myeloid Landscape to Induce Alveolar Macrophage-Mediated Control of Lung Metastasis

Nianxin Yang, Nicole Fong, David G. Hendrickson, John Balibalos, Kenneth J. Finn, Marcia N. Paddock, Jonathan D. Powell, Leanne Jade G. Chan, Jordan Brown, Shagun Gupta, Ka Man Li, Varahram Shahryari, P. Godfrey, Evangelia Malahias, Kayley Hake, Im-Meng Sun, J. Douglas O'Hara, Lolita Penland, Fiona E. McAllister, Marc Creixell, Aaron W. Stebbins, Fiona Harding, Po-Han Tai, Yue Liu, Jiaxi Wang, Wenjun Kong, James J. Lee, Samir Kharbanda, Chirag H. Patel, Tuan Andrew. Nguyen
article en

Abstract

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.

Cancer Research
Enzo Life Sciences (United States) (US)
Good health and well-being
Openalex Percentile: Top 18%
Protein Tyrosine Phosphatases
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