Macrophage pyroptosis has been identified as a critical pathological mechanism in inflammation-related atherosclerosis (AS). In this work, we have demonstrated that Zn2+ features the strongest anti-inflammatory performance by screening 10 representative metal ions, and the MTC1 agonists can trigger lysosomal Zn2+ release and inhibit pyroptosis in macrophages. Based on these findings, we further engineered a mucolipin TRP channel 1 (MTC1)-related therapeutic nanoplatform for endogenously triggering lysosomal zinc release to curb inflammation and block macrophage pyroptosis. This nanoplatform consists of mesoporous silica nanoparticles to deliver MTC1 agonists and carbon nanodots, which could synergistically exert antiatherosclerotic effect by scavenging toxic reactive oxygen species, inhibiting macrophage pyroptosis, modulating macrophage transition, and rebuilding atherosclerotic immune microenvironment. These findings demonstrate that macrophage pyroptosis can be efficiently blocked via leveraging self-lysosomal zinc pool, which provides the paradigm of lysosomal zinc modulation-involved nanotherapeutics for managing other inflammatory diseases.

Immune checkpoint therapy for colorectal cancer (CRC) has been found to be unsatisfactory for clinical treatment. Fecal microbiota transplantation (FMT) has been shown to remodel the intestinal flora, which may improve the therapeutic effect of αPD-1. Further exploration of key genera that can sensitize cells to αPD-1 for CRC treatment and preliminary exploration of immunological mechanisms may provide effective guidance for the clinical treatment of CRC.
In this study, 16S rRNA gene sequencing was analyzed in the fecal flora of both responders and no-responders to αPD-1 treatment, and the therapeutic effect was experimentally verified.
Pseudomonas aeruginosa was found to be highly abundant in the fecal flora of treated mice, and Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) in combination with αPD-1 was effective in the treatment of CRC through the induction of CD8+ T-cell immunological effects.
The clinical drug PA-MSHA can be used in combination with αPD-1 for the treatment of CRC as a potential clinical therapeutic option.
Copyright © 2025 Chen, Ruan, Zhao, Yi, Xiao, Tian, Cheng, Chen and Wei.

TNFα has long stood as a hallmark feature of both inflammatory bowel disease and arthritis with its therapeutic potential demonstrated in neutralizing monoclonal antibody treatments such as Infliximab. Due to the high global burden of latent Mycobacterium tuberculosis (TB) infections, prior to receiving anti-TNF therapy, patients testing positive for latent TB are given prophylactic treatment with anti-tuberculoid medications including the first described TB-selective antibiotic, Isoniazid. While this is common clinical practice to prevent the emergence of TB, little is known about whether Isoniazid modifies intestinal inflammation alone. The aim of this study, therefore, was to determine whether Isoniazid presents a novel TB-independent therapeutic option for the treatment of Crohn's disease (CD)-like ileitis and uncover new mechanisms predisposing the host to intestinal inflammation.
The transgenic TNFΔARE mouse model of Crohn's-like terminal ileitis was used. The impact of Isoniazid administration (10 mg/kg/day dose in drinking water) on disease development was monitored between 8 and 12 weeks of age using a variety of behavioral and serological assays. Behavioral and motor functions were assessed using the LABORAS automated monitoring system while systemic and local tissue inflammation were determined at experimental termination using multiplex cytokine analysis. Whole-mount tissue immunofluorescence and fluorescent in situ hybridization were used to qualify changes within the host as well as the microbial compartment of the ileum and associated mesentery. Proposed cellular mechanisms of altered cytokine decay were performed on isolated primary splenocytes in vitro using selective pharmacological agents.
Compared to age-matched wild-type littermates, TNFΔARE mice display prominent progressive sickness behaviors from 8 through 12 weeks of age indicated by reduced movement, climbing, and rearing. Prophylactic administration of Isoniazid (10 mg/kg/day) is effectively able to protect TNFΔARE mice from this loss of function during the same period. Analysis revealed that Isoniazid was able to significantly reduce both systemic and intestinal inflammation compared to untreated vehicle controls impacting the epithelial colonization of known pathobiont segmented filamentous bacteria (SFB). Reduction in terminal ileal inflammation was also associated to the diminished formation of precursor-tertiary lymphoid organs within the associated ileal mesentery which were found to be associated with endospores derived SFB itself. Finally, we reveal that due to their genetic manipulation, TNFΔARE mice display accelerated posttranscriptional decay of IL-22 mRNA resulting in diminished IL-22 protein production and associated downstream antimicrobial peptide production.
Isoniazid protects against the development of intestinal and systemic inflammation in the TNFΔARE model of terminal ileitis by limiting the expansion of mucosal SFB and progression of the associated microbial-driven inflammation. This work highlights a possible mycobacterial-independent function of Isoniazid in limiting CD pathophysiology through limiting the mucosal establishment of pathobionts such as SFB and the association of such microbe-derived endospores linked to the formation of ectopic tertiary lymphoid organs seen commonly in patients.
© The Author(s) 2025. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

Immune checkpoint blockade (ICB) therapy has emerged as a new therapeutic paradigm for a variety of advanced cancers, but wide clinical application is hindered by low response rate. Here we use a peptide-based, biomimetic, self-assembly strategy to generate a nanoparticle, TPM1, for binding PD-L1 on tumour cell surface. Upon binding with PD-L1, TPM1 transforms into fibrillar networks in situ to facilitate the aggregation of both bound and unbound PD-L1, thereby resulting in the blockade of the PD-1/PD-L1 pathway. Characterizations of TPM1 manifest a prolonged retention in tumour ( > 7 days) and anti-cancer effects associated with reinvigorating CD8+ T cells in multiple mice tumour models. Our results thus hint TPM1 as a potential strategy for enhancing the ICB efficacy.
© 2024. The Author(s).

Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor-specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE-driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T-cell acute lymphoblastic leukemia (T-ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T-ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto-oncogene 1, transcription factor (ETS1). Hematopoietic system-specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T-ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T-ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T-ALL cells, targeting the enhancer of the T-ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T-ALL cells, identifying potential new targets for therapeutic intervention.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.