Overcoming immunosuppression in the tumor microenvironment (TME) is crucial for developing novel cancer immunotherapies. Here, we report that IL-16 administration enhances the polarization of T helper 1 (Th1) cells by inhibiting glutamine catabolism through the downregulation of glutaminase in CD4⁺ T cells and increases the production of Th1 effector cytokine IFN-γ, thus improving anti-tumor immune responses. Moreover, we find that establishing an IL-16-dependent, Th1-dominant TME relies on mast cell-produced histamine and results in the increased expression of the CXCR3 ligands in tumor-associated macrophages (TAM), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). Cancer patients exhibit impaired production of IL-16, which correlates with poorer prognosis. Additionally, low IL-16 production is associated with unresponsiveness to immunotherapy in cancer patients. Collectively, our findings provided new insights into the biological function of IL-16, emphasizing its potential clinical significance as a therapeutic approach to augment anti-tumor immunity and sensitize ICB-based cancer immunotherapy.

An unlimited source of human pancreatic β cells is in high demand. Even with recent advances in pancreatic differentiation from human pluripotent stem cells, major hurdles remain in large-scale and cost-effective production of functional β cells. Here, through chemical screening, we demonstrate that the bromodomain and extraterminal domain (BET) inhibitor I-BET151 can robustly promote the expansion of PDX1 ⁺ NKX6.1 ⁺ pancreatic progenitors (PPs). These expandable PPs (ePPs) maintain pancreatic progenitor cell status in the long term and can efficiently differentiate into functional pancreatic β (ePP-β) cells. Notably, transplantation of ePP-β cells rapidly ameliorated diabetes in mice, suggesting strong potential for cell replacement therapy. Mechanistically, I-BET151 activates Notch signaling and promotes the expression of key PP-associated genes, underscoring the importance of epigenetic and transcriptional modulations for lineage-specific progenitor self-renewal. In summary, our studies achieve the long-term goal of robust expansion of PPs and represent a substantial step toward unlimited supplies of functional β cells for biomedical research and regenerative medicine.

Cell fate transition involves dynamic changes of gene regulatory network and chromatin landscape, requiring multiple levels of regulation, yet the cross-talk between epitranscriptomic modification and chromatin signaling remains largely unknown. Here, we uncover that suppression of N -acetyltransferase 10 (NAT10), the writer for mRNA N ⁴ -acetylcytidine (ac ⁴ C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac ⁴ C modification regulates the protein levels of a subset of its targets, which are strongly enriched for fate-instructive chromatin regulators, and among them, histone chaperone ANP32B is experimentally verified and functionally relevant. Furthermore, NAT10-ac ⁴ C-ANP32B axis can modulate the chromatin landscape of their downstream genes (e.g., key regulators of Wnt and TGFβ pathways). Collectively, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a critical layer of epitranscriptomic modulation and uncover a previously unrecognized, direct cross-talk between epitranscriptomic modification and chromatin signaling during cell fate transitions.

Osteoarthritis (OA) is the most prevalent joint disease, yet effective disease-modifying OA drugs (DMOADs) remain elusive. Targeting macrophage polarization has emerged as a promising avenue for OA treatment. This study identified skatole through high-throughput screening as an efficient modulator of macrophage polarization. In vivo experiments demonstrated that skatole administration markedly reduced synovitis and cartilage damage in both destabilization of medial meniscus (DMM)-induced OA mice and monosodium iodoacetate (MIA)-induced OA rats. Mechanistically, skatole activated signal transducer and activator of transcription 6 (Stat6) signaling, promoting M2 macrophage polarization, while inhibiting nuclear factor-κB (NFκB) and mitogen-activated protein kinase (MAPK) signaling pathways to suppress M1 polarization. RNA-sequencing analysis, targeted metabolomics, and mitochondrial stress tests further revealed that skatole treatment shifted macrophages toward oxidative phosphorylation for energy production. Additionally, it up-regulated genes associated with glutathione metabolism and reactive oxygen species (ROS) pathways, reducing intracellular ROS production. The CUT&Tag assay results indicated that the downstream transcription factor p65 of NFκB can directly bind to gene loci related to inflammation, oxidative phosphorylation, and glutathione metabolism, thereby modulating gene expression. This regulatory process is inhibited by skatole. At the chondrocyte level, conditional medium from skatole-treated M1 macrophages balanced anabolism and catabolism in mouse chondrocytes and inhibited apoptosis. In IL1β-treated chondrocytes, skatole suppressed inflammation and catabolism without affecting apoptosis or anabolism. Overall, skatole maintains immune microenvironment homeostasis by modulating macrophage polarization in joints and preserves cartilage function by balancing chondrocyte anabolism and catabolism, effectively alleviating OA. These findings suggest skatole’s potential as a DMOAD.

Severe acute pancreatitis (SAP) is a critical condition characterized by an imbalance between systemic inflammatory response syndrome (SIRS) and compensatory anti‐inflammatory response syndrome (CARS). Disruptions in intestinal microbiota exacerbate this imbalance; however, the mechanisms by which commensal bacteria regulate SAP‐induced SIRS and/or CARS remain unclear. This study reports that the abundance of the gut commensal Akkermansia is significantly reduced in fecal samples from patients with acute pancreatitis (AP) and is inversely associated with the severity of systemic inflammatory responses. Using Foxp3‐DTR and IL‐10‐KO mice, it is found that Akkermansia muciniphila and its derived protein Amuc_1409 can suppress SAP‐induced pancreatic and systemic inflammation by increasing peripheral regulatory T cells (Tregs) and enhancing the IL‐10 expression. Mechanistically, Amuc_1409 interacts with Ube2k to reduce the ubiquitination degradation of Foxp3, and it promotes the differentiation of Tregs and the production of IL‐10, effectively alleviating inflammation induced by SAP. These findings highlight A. muciniphila and its derivative Amuc_1409 as promising probiotic and biomolecule for managing acute pancreatitis and potentially other inflammatory conditions.