Leanne Jade G Chan

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. In this study, 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, interferon γ (IFNγ) production and responsiveness, and tumor-killing activity of AMs within metastatic lesions. Depletion of AMs diminished the antimetastatic 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 in which adaptive immunity is insufficient. Significance: Alveolar macrophages are potent anti-metastatic immune effectors that can be targeted with pharmacological PTPN1/2 inhibitors to amplify IFNγ-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

A covalent peptide ligand mimicking the binding motif in the E6AP protein selectively crosslinks to HPV16 E6 with quantitative conversion. This ‘reactide’ provides a starting point in the development of inhibitors against HPV-driven cancers.

In Pseudoalteromonas rubra, an unclustered biosynthetic gene encodes a di-iron oxygenase-like enzyme that catalyzes regiospecific C–H activation and cyclization of prodigiosin, yet is unrelated to the Rieske oxygenases that produce other cyclized prodiginines. Prodiginines, which are tripyrrole alkaloids displaying a wide array of bioactivities, occur as linear and cyclic congeners. Identification of an unclustered biosynthetic gene led to the discovery of the enzyme responsible for catalyzing the regiospecific C–H activation and cyclization of prodigiosin to cycloprodigiosin in Pseudoalteromonas rubra. This enzyme is related to alkylglycerol monooxygenase and unrelated to RedG, the Rieske oxygenase that produces cyclized prodiginines in Streptomyces, implying convergent evolution.