Bacterial multidrug resistance poses an urgent challenge for the treatment of critically ill patients developing ventilator-associated pneumonia (VAP). Phage therapy, a potential alternative when conventional antibiotics fail, has been unsuccessful in first clinical trials when used alone. Whether combining antibiotics with phages may enhance effectiveness remains to be tested in experimental models. Here, we use a murine model of Pseudomonas-induced VAP to compare the efficacy of adjunctive phage cocktail for antibiotic therapy to either meropenem or phages alone. Combined treatment in murine VAP results in faster clinical improvement and prevents lung epithelial cell damage. Using human primary epithelial cells to dissect these synergistic effects, we find that adjunctive phage therapy reduces the minimum effective concentration of meropenem and prevents resistance development against both treatments. These findings suggest adjunctive phage therapy represents a promising treatment for MDR-induced VAP, enhancing the effectiveness of both antibiotics and phages while reducing adverse effects.
© 2025. The Author(s).

Alveolar macrophages (AMs) are essential for maintaining lung homeostasis. However, their roles in respiratory infections have been controversial because the methods of depleting them have often suffered from poor cell selectivity. To resolve this problem, we here used VeDTR technology to generate a transgenic mouse line in which AMs can be specifically depleted using diphtheria toxin. When various respiratory infections were examined using this system, we found that AMs prevented the proliferation of Mycobacterium abscessus. This result differed from previous findings using clodronate liposomes to deplete macrophages. We also revealed that the disappearance of AMs contributes to the reduction of bacterial load in the lungs and that AMs are indispensable for GM-CSF-mediated defense against M. abscessus infection. Taken together, the development of an AM-specific depletion system has provided an opportunity to study the roles of AMs in various respiratory infections from a different perspective.
© 2025 The Author(s).

Aberrant activation of IL-18 signaling regulates tumor immune evasion and progression. However, the underlying mechanism remains unclear. Here, we report that long-chain acyl-CoA synthase 6 (ACSL6) is highly expressed in liver cancer and correlated with poor prognosis. ACSL6 promotes tumor growth, metastasis, and immune evasion mediated by IL-18, independent of its metabolic enzyme activity. Mechanistically, upon IL-18 stimulation, ACSL6 is phosphorylated by ERK2 at S674 and recruits IL-18RAP to interact with IL-18R1, thereby reinforcing the IL-18R1-IL-18RAP heterodimer and triggering NF-κB-dependent gene expression to facilitate tumor development. Furthermore, the up-regulation of CXCL1 and CXCL5 by ACSL6 promotes tumor-associated neutrophil and tumor-associated macrophage recruitment, thereby inhibiting cytotoxic CD8+ T cell infiltration. Ablation or S674A mutation of ACSL6 potentiated anti-PD-1 therapeutic efficacy by increasing the effector activity of intertumoral CD8+ T cells. We revealed that ACSL6 is a potential adaptor that activates IL-18-NF-κB axis-mediated tumor immune evasion and provides valuable insights for developing effective immunotherapy strategies for cancer.

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.
Copyright © 2024 Elsevier Inc. All rights reserved.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung cancer (NSCLC) is the most common subset. We previously found that infiltration of tumor inflammatory monocytes (TIMs) into lung squamous carcinoma (LUSC) tumors is associated with increased metastases and poor survival. To further understand how TIMs promote metastases, we compared RNA-Seq profiles of TIMs from several LUSC metastatic models with inflammatory monocytes (IMs) of non-tumor-bearing controls. We identified Spon1 as upregulated in TIMs and found that Spon1 expression in LUSC tumors corresponded with poor survival and enrichment of collagen extracellular matrix signatures. We observed SPON1+ TIMs mediate their effects directly through LRP8 on NSCLC cells, which resulted in TGF-β1 activation and robust production of fibrillar collagens. Using several orthogonal approaches, we demonstrated that SPON1+ TIMs were sufficient to promote NSCLC metastases. Additionally, we found that Spon1 loss in the host, or Lrp8 loss in cancer cells, resulted in a significant decrease of both high-density collagen matrices and metastases. Finally, we confirmed the relevance of the SPON1/LRP8/TGF-β1 axis with collagen production and survival in patients with NSCLC. Taken together, our study describes how SPON1+ TIMs promote collagen remodeling and NSCLC metastases through an LRP8/TGF-β1 signaling axis.