Yong Zhao

T helper 17 (T _H 17) lineage is governed by canonical transcriptional factors and plays a pivotal role in the pathogenesis of autoimmune diseases in both mice and humans. However, the precise orchestration of this transcriptional program remains poorly understood. Here, we identified a positive correlation between the expression of Dhx9, a nuclear helicase, and T _H 17 lineage during the progression of autoimmune diseases. Conditional deletion of Dhx9 in T cells significantly reduced T _H 17 differentiation and ameliorated the symptoms in mouse models of experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis (RA). Mechanistically, Dhx9 was essential for increasing chromatin accessibility at the Rorc and Il17 loci, thereby facilitating the binding of canonical factors SMAD2, SMAD3, STAT3 (signal transducer and activator of transcription 3), and IRF4 (interferon regulatory factor 4) to drive the transcription of these two core T _H 17-specific genes. We additionally identified Nono as an uncharacterized regulator of T _H 17 differentiation that acts dependent on its interaction with Dhx9. Meanwhile, IL-6 (interleukin-6)–STAT3 signaling promotes T _H 17 cell differentiation by up-regulating Dhx9 expression. We identified a potential small-molecule inhibitor of Dhx9, punicalagin, which effectively suppressed T _H 17 differentiation and EAE progression. These findings uncover a mechanism orchestrating the transcriptional program of T _H 17 lineage commitment and highlight its therapeutic potential for autoimmune disease intervention.

Chemokines play a critical role in regulating immune cell infiltration and their interactions with cancer cells in the tumor microenvironment (TME). Disrupted chemokine gradients influence immune cell recruitment and activation, as well as tumor cell proliferation, metastasis, and angiogenesis. By modulating these processes, chemokines shape the immune landscape of the tumor microenvironment, driving either immunosuppressive or immunostimulatory responses with corresponding pro- or antitumor effects. Dysregulated expression of chemokines and their receptors is strongly associated with tumor initiation, progression, and clinical outcomes. As a result, the chemokine receptor axis has gained prominence as a therapeutic target in cancer immunotherapy. This review explores chemokine expression profiles across various tumor types and their receptor-mediated interactions with immune cells. It also summarizes current strategies to therapeutically target chemokine signaling, both as standalone interventions and in combination with other treatment modalities.

Tissue-resident macrophages (RTMs), predominantly originating from embryonic progenitors, play a pivotal role in maintaining tissue homeostasis and immune regulation. Their functional diversity is shaped by both their developmental origins—including the yolk sac, fetal liver, and bone marrow—and the local tissue microenvironment. In this study, we identified a unique subset of RTMs in Lyz2cre-RosaYFP reporter mice that lack Lyz2 expression and persist long-term in peripheral tissues. These Lyz2-YFP- RTMs follow a distinct developmental trajectory, transitioning from Lyz2-YFP-CD117+CD45-AA4.1- early erythro-myeloid progenitors (EMPs) to Lyz2-YFP-CD117+CD45+AA4.1- intermediate EMPs in a Csf2rb-dependent manner. Transcriptional profiling reveals that yolk sac-derived Kupffer cells (KCs) lacking Lyz2 expression are enriched in genes associated with T cell chemotaxis and tumor immunity. Functionally, these Lyz2-never expressed (Lyz2-YFP-) KCs are preferentially localized within intratumoral regions, where they promote hepatocellular carcinoma progression by recruiting CD4+CD25+Foxp3+ regulatory T cells (Tregs) and inducing T cell exhaustion. Conversely, Lyz2-ever expressed (Lyz2-YFP+) KCs exhibit anti-tumor activity by enhancing effector CD8+ T cell function. Our findings unveil a long-lived subset of RTMs with sustained pro-tumorigenic potential, underscoring the critical role of their yolk sac-derived developmental trajectory in shaping their functional properties. This study provides novel insights into the ontogeny-dependent heterogeneity of RTMs and their dual roles in tumor immunity.

Pigs are increasingly recognized as promising candidates for clinical xenotransplantation and as large‐animal models for biomedical research; however, interspecies differences in gut microbiota, immune function, and metabolism remain major barriers. To address this, we established gut microbiota‐humanized (GMH) pigs by transplanting human fecal microbiota into antibiotic‐treated pigs. We systemically evaluated alterations in microbiota composition, serum metabolites, and immune cell profiles using integrated metagenomic, quasi‐targeted metabolomic and single‐cell transcriptomic (scRNA‐seq) analyses. Metagenomic profiling revealed a shift in the intestinal microbiota of GMH pigs toward a human‐like composition, characterized by enrichment of Bacteroidia and depletion of Bacilli . Metabolomic analysis showed that GMH pigs exhibited serum metabolite profiles more closely resembling those of humans. Among 423 detected serum metabolites, 136 that were lower in control pigs than in humans were upregulated in GMH pigs, whereas 79 that were elevated in control pigs decreased post‐transplantation. Notably, pathways related to tryptophan metabolism, bile acid biosynthesis, and fatty acid metabolism were enhanced in GMT pigs, while carbon‐related and glycolytic pathways were attenuated, indicating partial convergence toward human metabolic phenotype. Integration of microbial and metabolite data identified 20 and 33 metabolites associated with Bacteroidia and Bacilli , respectively. scRNA‐seq profiling of peripheral blood mononuclear cells demonstrated transcriptional and compositional remodeling of T cells, monocytes, and B cell subsets in GMH pigs. These findings demonstrated that human fecal microbiota can reshape both systemic metabolic and immune artitecture in pigs, offering a robust large‐animal platform for studying host‐microbiota interactions and advancing translational application in xenotransplantation and microbiome‐based therapeutics.

Macrophage polarization, a dynamic process crucial for immune responses and tissue homeostasis, is tightly regulated by transcription factors. Understanding the transcriptional regulation of macrophage polarization holds significant therapeutic implications for various diseases, including cancer, autoimmune disorders, and metabolic syndromes. Studies have shown that transcription factors, including signal transducer and activator of transcription (STAT), nuclear transcription factor-κB (NF-κB), peroxisome proliferator-activated receptors (PPARs), interferon regulatory factors (IRFs), BTB and CNC homology (BACH), CCAAT-enhancer binding proteins (C/EBPs), kruppel-like factors (KLFs), Cellular Myc (c-Myc), the SNAIL family, v-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog (Maf), and hypoxia-inducible factor alpha (HIFα), are highly involved in shaping macrophage polarization. Targeting transcription factors involved in macrophage polarization may provide promising avenues for immunomodulatory therapies aimed at restoring immune homeostasis and combating pathological conditions characterized by dysregulated macrophage activation. Here, we review the intricate transcriptional networks that govern macrophage polarization, highlighting the pivotal role of transcription factors in orchestrating these processes.

The thymus plays a crucial role in the generation of functional T cells, which are essential in adaptive immune responses. However, the involution, dysfunction, and even absence of the thymus induced by various factors such as aging, heredity, tumor, infection, and surgical removal, greatly impair or completely deprive the normal functions of the thymus and has been threatening the health of countless patients. Thus, reconstituting the thymus in these patients is remarkably necessary and urgent, in which thymus transplantation is viable, but the rare donors and related complications dramatically limit its clinical application. Other exogenous regeneration therapies, like sex steroid inhibition and cytokines treatments, usually have nonspecific, limited, and transient outcomes. By comparison, de novo cell-based strategies to reconstitute the thymus may be more feasible, which can generate fully functional thymuses usually using autologous cells without the dependence on limited thymus donors, thus avoiding transplant donor shortage as well as related complications, and overcome the defects of exogenous regeneration therapies. In this review, we summarized the progression in this field, including the generation of functional thymic epithelial cells (TECs), the clonogenic culture of TECs, stem cell treatment, and the construction of thymic organoids, to provide a global perspective for cell-based de novo thymus reconstitution.

Macrophages play essential roles in homeostasis and disease, and they were considered terminally differentiated cells that cannot proliferate. However, growing evidence shows that macrophages can self‐renew in homeostasis and multiple pathological states in vivo and artificial induction in vitro. With the rise of immune cell therapy based on macrophages, large‐scale in vitro expansion of macrophages has become more and more urgent. However, the proliferation of macrophages in vitro is still inefficient because of the heterogeneity of macrophages, complicated crosstalk between macrophages and their microenvironments, and poor understanding of macrophage proliferation regulations. In this review, we summarized the discoveries known to stimulate macrophage proliferation in vitro, including cytokines, small molecule compounds, metabolites, the composition of pathogens and apoptotic cells, natural product extracts, gene editing, and other factors, as well as related mechanisms. It can be concluded that the promotion of macrophage proliferation in vitro covers various approaches and mechanisms. However, it is still necessary to test more strategies and learn more macrophage proliferation mechanisms to achieve large‐scale engineering expansion of macrophages in vitro.