PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

Liu, Y.; Sun, I.-M.; Creixell, M.; Brown, J.; Kharbanda, S.; Lee, J. J.; Shahryari, V.; Hake, K.; O'Hara, J.; Finn, K. J.; Yang, N.; Penland, L.; Wang, J.; Li, K. M.; Balibalos, J.; Stebbins, A. W.; Godfrey, P. M.; Tai, P.-H.; Malahias, E.; Kong, W.; Fong, N.; Hendrickson, D.; Gupta, S.; Chan, L.; McAllister, F.; Patel, C. H.; Paddock, M. N.; Nguyen, T. A.; Harding, F. A.; Powell, J. D.

doi:10.64898/2026.02.25.707995

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bioRxiv · 10.64898/2026.02.25.707995

PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

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Abstract

Metastasis remains the leading cause of cancer mortality, yet effective therapies are limited. While therapeutic responses are influenced by organ-specific immune microenvironments, strategies to pharmacologically modulate these niches remain poorly defined. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrate that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell/spatial transcriptomics and functional assays reveal that AC484 promotes AM accumulation within metastatic lesions, elevates their IFN{gamma} production and responsiveness, and enhances their tumor-killing activity. Depletion of AMs diminishes the anti-metastatic efficacy of AC484. Mechanistically, inhibiting PTPN1/2 by AC484 amplifies IFN{gamma}-STAT1 signaling in AMs, while disrupting this pathway impairs their tumor control capability. 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. SignificanceAMs are potent anti-metastatic immune effectors functionally constrained by PTPN1/2. Pharmacologically inhibiting PTPN1/2 amplifies their IFN{gamma}-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

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Liu, Y., Sun, I.-M., Creixell, M., Brown, J., Kharbanda, S., Lee, J. J., Shahryari, V., Hake, K., O'Hara, J., Finn, K. J., Yang, N., Penland, L., Wang, J., Li, K. M., Balibalos, J., Stebbins, A. W., Godfrey, P. M., Tai, P.-H., Malahias, E., Kong, W., Fong, N., Hendrickson, D., Gupta, S., Chan, L., McAllister, F., Patel, C. H., Paddock, M. N., Nguyen, T. A., Harding, F. A., Powell, J. D.. 2026-02-26. PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis. https://doi.org/10.64898/2026.02.25.707995

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