Caspase-8 is essential for maintaining organismal integrity by preventing cell death and subsequent inflammation in specific epithelial and endothelial tissues. Here, we show that caspase-8 also controls a systemic, cell death-independent inflammatory pathway that is constitutively active during homeostasis. In vivo, selective caspase-8 inhibition produces, in the absence of other stimuli, marked neutrophilia driven by circulating proinflammatory and chemotactic cytokines and promotes bacterial clearance during infection. In vitro, caspase-8 inhibition triggers in neutrophils, but not in macrophages, a profound transcriptional response associated with the release of IL-1β and other cytokines. This process requires tonic TNF-α production by neutrophils, which acts autocrinally to sequentially activate RIPK1, RIPK3, MAPKs, and NF-κB. The IL-1β release induced by caspase-8 inhibition requires gasdermin D and neutrophil serine proteases, but not canonical inflammasome components. Our data uncover the mechanistic features of a neutrophil-centric, proinflammatory pathway that can be therapeutically targeted to augment host defenses against pathogens.
© 2026. The Author(s).

Interleukin 1 (IL1) plays dual functions in cancer. It promotes cancer-related inflammation and progression but also influences leukocyte functional activation. IL1 receptor 2 (IL1R2) functions as an IL1 decoy receptor, inhibiting IL1 activity. In this study, we investigated the contribution of IL1R2 in tuning IL1-dependent effects in mouse models of cancer, including colorectal cancer, lung cancer, and primary and metastatic transplantable and chemically induced sarcoma. Even though the prominent role of IL1 is protumoral, IL1R2 deficiency was selectively associated with reduced sarcoma growth, whereas it was irrelevant in other preclinical models investigated. IL1R2 deficiency was associated with a massive infiltration of neutrophils in the tumor, neutrophilia, and increased extramedullary emergency granulopoiesis. Neutrophils were crucial for tumor control in IL1R2-deficient mice. Immunophenotypic and transcriptional profiling of sarcoma-infiltrating neutrophils revealed that IL1R2 deficiency was associated with higher expression of activation or maturation markers and gene expression reprogramming, with downregulation of pathways associated with protumoral functions. In patients with sarcoma, the IL1R2 deficiency gene signature correlated with better clinical outcomes. Thus, this study shows that IL1R2 tunes IL1-driven cancer-associated emergency granulopoiesis and neutrophil functional activation to an antitumor mode in sarcomas and reveals the antitumor potential of neutrophils in this tumor.
©2026 The Authors; Published by the American Association for Cancer Research.

Tuberculosis is caused by the bacterium Mycobacterium tuberculosis (Mtb). Emergence of drug resistance in Mtb requires continuous enrichment of anti-tubercular medication. Inclusion of host-directed therapies holds considerable promise in this context. Sorafenib (SRB) is a multi-kinase inhibitor targeting VEGF receptor kinase, Raf, MEK, and extracellular signal-regulated kinase (ERK) signaling cascade to treat several types of cancer, including hepatocellular carcinoma. We have previously established that SRB allosterically inhibits ornithine acetyltransferase (MtArgJ), an essential enzyme in the arginine biosynthesis pathway of Mtb, thereby limiting bacterial growth in culture at a minimum inhibitory concentration of 10 µg/mL. The current work focuses on how SRB at the dose of 30 mg/kg body wt inhibits the pathogenicity and survival of bacteria in a preclinical mouse model of tuberculosis by inducing pro-apoptotic and immunomodulatory mechanisms in the host. We observed that SRB treatment promotes apoptosis in Mtb-infected and -uninfected THP-1 cells, human monocyte-derived macrophages. Concomitantly, SRB treatment reduces infection-associated necrosis in the Mtb-infected THP-1 cells. We further noted the upregulated expression of pro-apoptotic proteins during SRB treatment in preclinical mouse models. In addition, we investigated the expression of pro- and anti-inflammatory cytokines and immunomodulation in lung tissues treated with SRB. Interestingly, SRB treatment increased the number of arginase 1-positive macrophages, which are reckoned to enhance tissue healing. In conclusion, our research discloses that SRB is helpful in both lowering the tubercular burden and accelerating recovery of damaged tissue by harnessing the host immune response.IMPORTANCEHost-directed therapies hold considerable promise for treating drug-resistant Mycobacterium tuberculosis (Mtb). In this context, the induction of apoptotic and immunomodulatory responses in the host by sorafenib (SRB) is demonstrated here to compromise the survival and pathogenic potential of Mtb in a preclinical mouse model of TB and in Mtb-infected and -uninfected THP-1 cells. Concurrently, the infection-associated necrosis in the Mtb-infected THP-1 cells is also reduced. Furthermore, arginase 1-positive macrophages, which are known to enhance tissue healing, are increased in SRB-treated groups. Thus, SRB treatment not only lowers the tubercular load but also aids in healing damaged tissues by leveraging the host immunity.

Second mitochondrial activator of caspase (SMAC) mimetics (SMACm) and bromodomain and extra-terminal domain (BET) inhibitors (BETi) are two distinct classes of novel anticancer therapeutics. So far, broad clinical benefit for either monotherapy has not been achieved, calling for effective combination strategies. We show that the combination of BI 891065, a monovalent oral SMACm antagonist of inhibitor of apoptosis protein 1 (cellular inhibitor of apoptosis protein 1 [cIAP1]), and BI 894999, a potent and selective oral BETi, significantly impaired cancer cell proliferation irrespective of tissue context. Interestingly, we observed various forms of cell death pointing at distinct, but functionally converging, modulation of cell death-promoting pathways. A multi-omic analysis using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and advanced flow cytometry of a syngeneic model of pancreatic ductal adenocarcinoma (PDAC) unveils distinct phenotypic correlations of augmented anti-tumor immunity and a substantially reduced immunosuppressive tumor microenvironment (TME). Collectively, this study presents BETi and SMACm as a promising drug combination for patients with cancer with a multi-layered impact on both tumor cell-intrinsic and TME-dependent mechanisms.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

Regulatory T (Treg) cells are a specialized CD4+ T cell lineage with essential anti-inflammatory functions. Analysis of Treg cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector Treg cell transcriptional programs. Attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR-independent functionality seems to facilitate the terminal differentiation of a population of colonic effector Treg cells that are distinguished by stable expression of the immunomodulatory cytokine IL-10. Functional studies show that this subset of effector Treg cells, but not their expression of IL-10, is indispensable for colonic health. These findings identify core features of the terminal differentiation of effector Treg cells in non-lymphoid tissues and their function.
© 2025. The Author(s).