The liver-secreted protein fibrinogen-like protein 1 (FGL1) is a ligand of the coinhibitory receptor LAG3 on T cells; however, Fgl1[-/-] mice exhibit autoimmune features distinct from those of Lag3[-/-] mice. Here, we examined whether FGL1 acts via receptors beyond LAG3 to regulate autoimmunity. Recombinant FGL1 administration reduced autoimmune symptoms in B6/lpr lupus-like mice. This was associated with diminished antigen-specific IgM responses and B cell numbers. Genome-wide surface proteome screening identified the tumor necrosis factor receptor (TNFR) family member transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a receptor for B cell-activating receptors BAFF and APRIL, as a receptor for FGL1. TACI bound FGL1 via an N-terminal site not required for BAFF and APRIL interaction. The impact of FGL1 administration on B cell numbers and autoimmune phenotypes was lost in Taci[-/-] mice. Mechanistically, FGL1 promotes TACI internalization, thereby regulating receptor availability for activating ligands. Thus, FGL1 regulates an innate-like subset of B cells via modulating TACI availability, with implications for autoimmunity and inflammation.

Bile acids have emerged as compartmentalized immunometabolic signals that link host metabolism, microbial ecology, and tumor immunity. Altered bile acid profiles are common across malignancies and are associated with tumor progression, immune tone, and responsiveness to immunotherapy. Bile acids shape the gut microbiota, and in turn, microbial enzymes diversify the bile acid pool, generating distinct bile acid species that can remodel the tumor immune landscape. Depending on species identity, concentration, and context, bile acids can support immune surveillance or enforce immune escape by reshaping antigen priming, lymphocyte fitness, myeloid suppression, and immune cell trafficking. Here, we synthesize emerging concepts defining a microbiome-bile acid-immune axis in cancer and highlight therapeutic opportunities to harness bile acid signaling as next-generation strategies in oncology.

Metastatic microenvironments vary widely not only in their biochemical composition but also in their mechanical properties. Here, we examined how the mechanical rigidity of the metastatic niche affects metastases seeding and the local efficacy of antitumor immunosurveillance. Cancer cells stiffened in response to increasing environmental rigidity, a biophysical change that mechanically sensitized them to killing by cytotoxic lymphocytes. In immunodeficient mice, rigidity sensing by cancer cells yielded robust bone colonization, accompanied by marked stiffening of the cancer cells themselves. Conversely, in immunocompetent hosts, stiffer cancer cells were selectively eliminated, and bone metastasis was suppressed. In patients, metastatic cell stiffness was associated directly with environmental rigidity and inversely with immune infiltration. Expression of Spp1, encoding the secreted glycoprotein osteopontin, defined a subset of cancer cells that expanded in the bone, and deletion of Spp1 limited environmentally induced cancer cell stiffening, bone colonization, and immune vulnerability. Thus, environmental mechanosensing regulates both metastases seeding and antitumor immunity, providing an immunological basis for metastatic site selection.

Peripheral differentiation of regulatory T (pTreg) cells promotes immunological tolerance to obligate non-self, such as food or symbiotic microbes. We examined the relative importance of TCR recognition vs. environmental cues, leveraging CRISPR-based TCR editing of primary T cells with a large TCR panel, assessing pTreg cell differentiation induced by self-, microbial, or dietary antigens. All antigen classes drove stable pTreg cell differentiation, which varied with TCR origin: TCRs derived from Treg cells enabled pTreg cell differentiation more effectively than those from conventional T cells. TCRs recognizing self-, microbial, or dietary antigens elicited distinct pTreg cell phenotypes: Helios[+], RORγ[+], or both. Different TCR-antigen pairs established distinct transcriptional programs. These differences traced to the types of antigen-presenting cells (APCs) involved-food-reactive TCRs depended predominantly on RORγ[+] APCs and self-reactive TCRs depended on conventional dendritic cells. Thus, TCR specificity is a primary determinant of CD4[+] T cell fate and phenotype, integrating antigen specificity and presentation context, providing a framework to design TCR-based tolerogenic immunotherapies.

Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.

Toll-like receptors (TLRs) are considered general sensors of bacterial encounters. Here, we examined whether other pattern recognition receptors are commonly activated during bacterial infection. TLR-independent interferon (IFN) responses were induced in macrophages in response to diverse bacterial encounters. Of the cytoplasmic receptor families examined, the cyclic dinucleotide (CDN) sensor STING was required for IFN responses to evolutionarily diverse bacteria. Various bacterial CDNs were present in murine tissues; these activated stimulator of interferon genes (STING) after bacteriolysis in phagolysosomes in a manner requiring two CDN transporters. Importantly, bacterial CDNs were increased in colonic biopsies from patients with inflammatory bowel disease. Systemic delivery of dead, CDN-laden bacteria promoted anti-tumor immunity in mice. Detection of diverse CDNs, including pyrimidine-based CDNs, was an evolutionarily conserved feature of STING, with distinct binding modes for purine- and pyrimidine-based CDNs. Thus, a phagocytosis-CDN-STING connection places cytoplasmic sensing as a common outcome of host-bacteria interactions that set the immune tone of a tissue, with implications for host defense.

High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary lymphoid organs (SLOs). They are equipped with high amounts of peripheral node addressin (PNAd), harboring carbohydrate structures that serve as L-selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms that maintain HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises lymphotoxin beta receptor (LTβR) signaling and the unfolded protein response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LTβR blockade impair HEV function and reduce skin inflammation in psoriasis-affected mice by limiting immune infiltration and cytokine release. Our work reveals that autophagy safeguards HEV identity and function during inflammation.

Macrophage activation and tissue adaptation involve precise transcriptional control by lineage-determining transcription factors (LDTFs) and stimulus-dependent TFs. The heme-regulated transcriptional repressor BACH1 clusters with myeloid LDTFs in unstimulated macrophages, suggesting a role in shaping macrophage identity and function. We found that BACH1 bound to both inactive and active regulatory regions, including latent enhancers. BACH1 recruited the NuRD complex and had dual functions, establishing early chromatin accessibility while actively repressing transcription. Upon inflammatory stimulation, BACH1 rapidly redistributed in cis to nearby promoters, reshaping chromatin occupancy, motif specificity, and enhancer-promoter interactions. BACH1 constrained 3D chromatin architecture, limiting enhancer mobility and TF complex dynamics. In vivo, Bach1 deletion impaired macrophage polarization and tissue adaptation and limited resilience during systemic and regenerative inflammation. Thus, BACH1 acts as an early chromatin accessibility-priming factor while actively repressing transcription-a regulatory activity that can be defined as pioneer repression-thereby shaping the macrophage epigenome in response to inflammatory and tissue contexts.

The vagus nerve regulates inflammation via sensory-motor arcs. While vagal sensory neurons relay signals from within the body (interoception), whether external inputs can regulate visceral neuroimmune responses (exteroception) remains poorly understood. We unveiled a skin-lung reflex by which sensory neurons from the auricular skin suppressed Alternaria alternata-induced allergic airway inflammation. Viral and chemical neural tracing revealed distinct sensory projections from the vagal ganglia to the auricular skin. Pharmacologic, chemogenetic, and optogenetic activation of auricular transient receptor potential vanilloid 1 (TRPV1)+ afferents attenuated type 2 allergic lung inflammation, including group 2 innate lymphoid cell, eosinophil, and type 2 cytokine responses in the airway. Conversely, silencing of these sensory neurons via the skin exacerbated lung inflammation, and immunosuppression of airway inflammation was dependent on the neuropeptide calcitonin gene-related peptide (CGRP)β. These findings reveal an evolutionarily conserved somato-visceral reflex by which exteroceptive inputs impact visceral inflammation. Thus, transcutaneous neuromodulation may represent a therapeutic strategy to treat visceral inflammation.

The commensal yeast Candida albicans is a major inducer of human mucosal Th17 cells. How C. albicans drives Th17 cell responses at homeostasis, and whether such responses contribute to inflammatory diseases, remains poorly understood. Here, we showed that C. albicans-reactive Th17 cells targeted a limited set of proteins enriched in fungal extracellular vesicles. At homeostasis, these cells predominantly resided in the oral mucosa. However, T cell receptor profiling revealed shared clonotypes across oral and gut tissues, with C. albicans being a major driver of this repertoire overlap. In patients with Crohn's disease, C. albicans-specific Th17 cells with features of oral priming were enriched in intestinal tissues, where they retained their focused antigen specificity but acquired pathogenic Th17 cell traits. Together, our results reveal a stable, antigen-restricted C. albicans Th17 subset that is shared across mucosal sites and undergoes functional adaptation in the inflamed intestine. These cells represent a potential target for immune modulation in Crohn's disease.

While pregnancy suppresses systemic immunity to tolerate the fetus, adaptations of the gut remain unclear. In a recent issue of Nature, Huang et al. show that reproduction increases intestinal eosinophils, shifting intestinal stem cell fate toward goblet cells and protection from enteric pathogens. This phenomenon begins in pregnancy, peaks during lactation, and persists weeks after lactation cessation.

Metabolic alterations and neutrophils define the pre-metastatic niche, but the mechanisms connecting them remain incompletely understood. In this issue of Immunity, Qian et al. show that endothelial-derived palmitate induces neutrophils to release lipocalin-2, disrupting vascular integrity and promoting lung metastasis.

Extracellular ATP (eATP) is an immunogenic danger signal. In this issue of Immunity, Hu et al. report that in the tumor microenvironment, eATP signals through the receptor P2RY2 on cancer cells, triggering the COX-PGE2 pathway and thereby immune suppression and immunotherapy resistance. These findings identify eATP as the upstream signal driving PGE2 expression, with therapeutic implications.

Similar to CD8[+] T cells, stem-like CD4[+] T cells sustain responses to tumors, chronic infections, and inflammation. In this issue of Immunity, Wen et al. and Agesta et al. reveal EOMES as a critical regulator of stem-like CD4[+] T cell maintenance and differentiation.

Aging and chronic inflammation alter hematopoiesis, impacting the hematopoietic progenitor populations in the bone marrow. In this issue of Immunity, Yao et al. show that the canonical type 2 cytokine interleukin 4 reverses age-related hematopoietic and physiologic effects by rebalancing progenitor fates.