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PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis [CosMx SMI]

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 IFNγ 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 IFNγ-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE337933 | GEO | 2026/09/02

REPOSITORIES: GEO

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

Project description: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 IFNγ 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 IFNγ-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.

2026-09-02 | GSE337931 | GEO

Effect of Ptpn1/2 knockout on the transcriptome of unstimulated or IFN-beta stimulated B16-OVA cells

Project description:Immune evasion by cancer cells remains a major barrier to the success of immune checkpoint blockade (ICB). Here, we identify the phosphatases PTPN1 and PTPN2 as cooperative regulators of tumor immune resistance. Dual genetic ablation or pharmacologic inhibition of PTPN1/2 enhances Type I and II interferon signaling, MHC-I and CXCL9 expression, and sensitizes tumor cells to cytotoxic T lymphocyte–mediated killing. The small-molecule inhibitor KQ791 phenocopies these effects and synergizes with anti-PD1 therapy to suppress tumor growth in murine models, including immunotherapy-refractory cancers. Mechanistically, PTPN1/2 loss augments STAT1/3/5 signaling and primes cancer cells for immunogenic cell death via IFNγ/TNFα-induced pathways. Moreover, PTPN1/2 inhibition enhances antigen release and cross-presentation, promoting robust antigen-specific CD8⁺ T cell responses. These findings highlight PTPN1&2 as essential mediators of cancer immune evasion and support their inhibition as a strategy to broaden the effectiveness of immune checkpoint blockade in solid tumors.

2026-07-28 | GSE297993 | GEO

Ptpn1 loss leads to B cell acute lymphoblastic leukemia

Project description:Mice with NHD13 expression and homozygous Ptpn1 loss developed BCP-ALL with a penetrance of 70%, suggesting that Ptpn1 can function as a tumor suppressor gene in this context. Moreover, NHD13/Ptpn1+/- mice that developed BCP ALL typically showed a loss of the Ptpn1 wild type allele in leukemia cells, supporting the assertion that Ptpn1 can function as a tumor suppressor gene.

2026-08-19 | GSE344032 | GEO

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_ATACseq]

Project description:Immune checkpoint blockade is effective for some cancer patients, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets and in particular, the active site has been considered undruggable. Here, we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In murine cancer models resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes NK and CD8+ T cell function by enhancing JAK-STAT signaling and reducing T cell dysfunction. PTPN2/N1 inhibitors offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (NCT04777994). More broadly, our study shows that small molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics targeting this important class of enzymes.

2023-07-14 | GSE237376 | GEO

The PTPN2/N1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [TIL_RNAseq]

2023-07-14 | GSE237377 | GEO

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

Project description:The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity

| PRJNA994840 | ENA

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

Project description:The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

| PRJNA994836 | ENA

The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity [SK_RNAseq]

Project description:AC484 is a first-in-class, orally bioavailable, potent PTPN2/N1 active site inhibitor. In order to investigate the response of AC484 and IFNg treatment on wild type and PTPN2/N1 dual deletion B16F10 cells, these tumours were transcriptionally profiled.

2023-07-14 | GSE237371 | GEO

Expression changes induced by PTPN1 knockdown in KM-H2 cells

Project description:Gene expression data for shRNA PTPN1 knockdown vs. Non-silencing in the classical Hodgkin lymphoma-derived cell line KM-H2

2014-01-17 | GSE54157 | GEO

RNA-seq analysis of IL-10 treatment of wildtype and Ptpn1-/- knockout peritoneal macrophages

Project description:We report here the deep sequencing of the mRNA from peritoneal exudate cells (macrophages) purified from wildtype or Ptpn1 (PTP1B) knockout mice, either treated or untreated with IL-10. In periotenal macrophages IL-10 activates the transcription factor STAT3 to execute and anti-inflammatory gene expression programme. The tyrosine phosphatase PTPN1 targets STAT3 for dephosphorylation and leads to the deactivation of STAT3. In this study we examined the role of PTP1B in controlling the normal homeostatic level phosphorylation of STAT3 by comparing the IL-10/STAT3-mediated anti-inflammatory gene expression programme. We find that loss of PTP1B leads to an up-regulation of the activity of STAT3, both at the level of phosphorylation and also in enhanced expression of anti-inflammatory gene products. RNA-seq of wildtype and Ptpn1 (PTP1B) knockout mouse peritoneal macrophages, treated or untreated with IL-10

2014-05-12 | E-GEOD-49449 | biostudies-arrayexpress

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