interferon

Correction: Deubiquitinase USP35 restrains STING-mediated interferon signaling in ovarian cancer.

Zhang Jiawen J, Chen Yunfei Y, Chen Xianfei X, Zhang Wen W et al.

Lost and found in translation: the value of the human imiquimod model.

Meijs Anouk C AC, van den Noort Juliette A JA, Assil Salma S, Klarenbeek Naomi B NB et al.

Topical imiquimod (IMQ), a Toll-like receptor (TLR) 7 agonist, induces transient cutaneous inflammation and is widely used in preclinical research as a 'psoriasis-like' mouse model. However, accumulating evidence indicates substantial divergence between IMQ-driven biology and human plaque psoriasis pathogenesis. To bridge this translational gap, we compare here the experimental conduct, readouts and mechanistic insights engaged by IMQ challenge in mice vs. healthy human participants. Importantly, molecular and cellular analyses indicate that IMQ predominantly activates interferon regulatory factor (IRF) signalling in humans, rather than NF-κB pathways as observed in animals. Moreover, differences in neutrophil response and complement activation were also identified. These discrepancies may reflect interspecies variation in TLR7 expression as well as methodological differences between the animal and human IMQ model. Despite certain limitations related to psoriasis translatability, the human IMQ model has demonstrated translational relevance in several early phase clinical trials. It represents a valuable tool for evaluating target engagement and characterizing downstream pharmacodynamic effects of novel compounds, particularly those targeting the TLR7-IRF-type I interferon axis. In conclusion, the human IMQ model can serve as valuable mechanistic model driving disease-related pathways, rather than as a proxy for plaque psoriasis disease biology. Fit-for-purpose benchmarking and method standardization are essential to maximize translational utility of the IMQ model.

The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.

Liu Xiaoguang X, Xu Miaomiao M, Wang Huan H, Wang Haozhe H et al.

Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS-STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear. We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle-specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing. Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle-specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle-specific cGAS-deficient mice showed reduced expression of muscle atrophy-associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes. These findings support a role for cGAS-STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS-STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.

Non-genetically reprogrammed meta-neutrophils potentiate chemo-immunotherapy against lung metastatic triple-negative breast cancer.

Hao Meixi M, Hu Qifan Q, Li Xiuqi X, Chen Yijun Y et al.

Neutrophils (NEs) exhibit significant therapeutic potential in tumor therapy owing to their distinct advantages. In clinical trials, however, adoptive transfer of NEs shows limited efficacy against advanced solid tumor, partially owing to the unsatisfactory antitumor potency. Besides, the phenotype plasticity of NEs in tumor environment restricts their direct application. Here, we report a non-genetic reprogramming strategy via sequential interferon gamma (IFNγ) training and Abraxane arming to obtain meta-NEs, which hold persisted antitumor phenotype of NEs and potentiated chemo-immunotherapy effect. We find that meta-NEs demonstrate enhanced accumulation in lung metastases and thus harness the strengthened tumoricidal and immunostimulatory potency of NEs and the cytotoxicity of Abraxane to achieve safe and potentiated chemo-immunotherapy against lung metastatic triple-negative breast cancer. In short, we provide a non-genetic reprogramming strategy for NEs to generally improve their antitumor efficacy regardless of donors, which puts forward rationale for the clinical development of NEs in metastatic breast cancer therapy.