In vitro diagnostics of drug hypersensitivity reactions comprises different tests that can add important information for identifying the culprit drug. Depending on the patients' clinical history and underlying immune mechanisms, these tests can be classified into immediate-type and late-type in vitro assays. While they are currently mostly not part of routine diagnostics, knowledge of when to apply which test and what distinct benefits and specific limitations each assay carries, can be helpful when considering the referral of patients with adverse drug reactions for appropriate further testing to specialized centers.

Systemic iron homeostasis is governed by hepcidin through regulation of the iron exporter ferroportin. Hepcidin expression is primarily regulated by the bone morphogenetic protein (BMP)-SMAD signaling pathway, which integrates signals from iron status, erythropoietic demand, and inflammation. Fibrinogen-like protein 1 (FGL1) has recently emerged as a hepatocyte-derived regulator of this axis. FGL1 is a secreted hepatokine which is induced by hypoxia, inflammatory signaling, and metabolic stress. FGL1 suppresses hepcidin by binding BMP ligands, thereby attenuating BMP-SMAD signaling and reducing HAMP transcription. This mechanism complements erythroferrone (ERFE), providing a sustained hepatocyte-derived signal during anemia/ hypoxia and erythropoietic stress. Beyond iron regulation, FGL1 functions as a ligand of lymphocyte activation gene-3 (LAG-3), linking iron metabolism with immune checkpoint pathways. This dual role establishes FGL1 at the interface of metabolic and immune regulation. Dysregulation of FGL1 has been implicated in multiple disease states. In chronic kidney disease, reduced circulating FGL1 may contribute to hepcidin excess and functional iron deficiency. In autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's disease, FGL1 exhibits context-dependent effects on immune regulation. In cancer, tumor-derived FGL1 promotes immune evasion through the FGL1-LAG-3 axis and is associated with resistance to PD-(L)1 blockade and poor clinical outcomes. This review provides a comprehensive overview of FGL1 structure, regulation, and function. It also highlights its emerging role as a mediator linking iron metabolism and immune regulation, as well as its potential as a biomarker.

Interleukin (IL)-10-producing B cells represent an archetype for the regulatory functions of B cells. Here, we review the cell-surface receptors and transcriptional regulators that control IL-10 expression in B cells and enable their regulatory function in vivo. To integrate available data, we propose a three-layer competence-execution-stabilization (CES) framework for IL-10-mediated B cell regulation. We propose that B cell receptor signaling during B cell development and at homeostasis contributes to establishing high IL-10 competence in selected B cell subsets at steady state. Execution of IL-10 expression and regulatory function then requires the integration of canonical B cell activation pathways with environmental signals and involves transcriptional programs that are largely intertwined with those controlling plasma cell differentiation. Notably, chemically induced IL-10-producing B cells progressively differentiate into IL-10-producing plasma cells and acquire homogeneous and stable IL-10 expression. Together with LAG-3[+]CD138[hi] plasma cells, these cells represent the only B cell populations described so far in which IL-10 expression approaches population-wide penetrance. We therefore propose that plasma cell differentiation may constitute an attractor state for stabilizing IL-10-producing regulatory programs. The CES framework provides a conceptual basis for investigating the diversity and regulatory functions of IL-10-expressing B cell states in vivo.

As a T-cell receptor co-stimulatory protein, signaling lymphocyte activation molecule family 6 (SLAMF6) is a member of the immune cell activating receptor family and is expressed on T cells, B cells, natural killer cells (NK cells), and tumor cells. To date, the biological functions and clinical significance of SLAMF6 in certain solid tumors remain to be elucidated. We analyzed the transcriptional expression pattern of SLAMF6 and its relationship with clinical outcomes using clinical specimens and pancancer databases. Next, multispectral immunofluorescence was applied to assess the correlation between SLAMF6 expression and CD8[+] T-cell activation and infiltration in clinical samples, with additional validation through immune-infiltration analysis. In parallel, using a colorectal cancer xenograft model, we examined how upregulation of SLAMF6 combined with immune-checkpoint blockade (anti-PD-L1) influences immunotherapy efficacy. Ultimately, our findings indicate that SLAMF6 modulates CD8[+] T-cell activation and infiltration through the STAT1/CXCL10 axis, thereby enhancing the recruitment of these effector cells to tumor sites.

Invariant natural killer T (iNKT) cells are CD1d-restricted T cells that recognize lipid antigens. Studies of analogs of a prototypic iNKT cell antigen, α-galactosylceramide (α-GalCer), have shown that ceramide structure affects the activities of mouse iNKT cells recognizing the antigen. However, the impact of antigen structure on human iNKT cell activities is less well studied. This study evaluated the antigenicity of eight novel synthetic sulfatide-based lipids with fluorobenzene at the acyl chain terminus and a variety of sphingoid base structures. Using CD1d-tetramers, we evaluated TCR recognition in ex vivo iNKT cells from healthy donors' peripheral blood mononuclear cells (PBMCs). One analog, SAP-3, was commonly recognized by iNKT cells from all donors. SAP-3 increased the proportion of CD69[+]CD25[+] iNKT cells in a CD1d-dependent manner and triggered IL-2 production. Furthermore, SAP-3-activated ex vivo iNKT cells increased the frequency of polyfunctional antigen-specific CD8[+] T cells (IFN-γ[+]IL-2[+]TNF-α[+]) in PBMC stimulation culture. Importantly, repeated in vitro stimulation with SAP-3 did not induce iNKT-cell functional anergy, unlike α-GalCer; instead, SAP-3 increased IFN-γ-producing iNKT cells. These findings suggest that the structures of sulfatide analogs critically influence their immunogenicity. SAP-3 emerges as a novel human iNKT agonist that enhances antigen-specific CD8[+] T cell responses and represents a promising vaccine and adjuvant candidate.

Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) is a highly effective treatment option for patients with relapsed refractory multiple myeloma (RRMM). However, reliable biomarkers predicting long-term treatment response remain elusive. Germline single-nucleotide polymorphisms (SNPs) in immune checkpoint regulators, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and lymphocyte activation gene 3 (LAG3) may affect CAR T-cell functionality and clinical efficacy. We conducted a retrospective analysis of 87 patients with RRMM treated with BCMA-directed CAR T-cells at a single academic center between May 2021 and September 2025, evaluating the impact of CTLA4 rs231775 and LAG3 rs870849 on relapse, progression-free survival (PFS), and overall survival (OS). The minor allele rs231775 of CTLA4 was present in 48%, while the minor allele of LAG3 rs870849 was observed in 87% of patients. Carriers of the CTLA4 rs231775 minor allele demonstrated lower relapse (40 vs. 53%) and mortality rates (31 vs. 44%) compared with major allele homozygotes, accompanied by significantly prolonged PFS and OS. Likewise, patients homozygous for the LAG3 rs870849 minor allele experienced reduced relapse (36 vs. 52%) and mortality rates (28 vs. 42%), significantly longer PFS, and a trend toward improved OS relative to carriers of the major allele. In conclusion, in our study, the minor alleles of CTLA4 rs231775 and LAG3 rs870849 were associated with superior clinical outcomes following BCMA-directed CAR T-cell therapy in RRMM patients. These findings suggest to further evaluate whether immune checkpoint SNPs could be biomarkers predicting response to BCMA-directed CAR T-cell therapy in MM which needs prospective studies and validation.

Decidual natural killer (dNK) cells are the predominant lymphocyte population at the maternal-fetal interface during early pregnancy, where they support placentation, vascular remodelling and immune tolerance. Despite their abundance, the mechanisms governing their proliferative state remain poorly understood. Here, we show that first-trimester dNK cells reside in a stable non-cycling state characterized by G0/G1 arrest, suppression of proliferation-associated transcriptional programmes and attenuated kinase signalling. Unlike peripheral blood NK (pNK) cells, dNK cells did not proliferate in response to IL-15 stimulation or exposure to human cytomegalovirus-infected autologous decidual stromal cells, indicating entry into cell-cycle is actively restrained within the decidual compartment. Mechanistically, dNK cells exhibited altered CD244 splice-variant usage together with markedly reduced expression of the adaptor protein SAP (SH2D1A), accompanied by broad attenuation of Src, MAPK, and mTOR signalling. Blockade of the CD244-CD48 axis promoted dNK-cell cycle entry and modulated ERK and p38 activation, identifying this signalling axis as a regulator of proliferative quiescence. Furthermore, decidua-associated cytokines remodelled CD244 splice-variant usage and receptor expression in pNK cells, demonstrating that soluble microenvironmental cues are sufficient to reprogramme NK-cell signalling. Together, these findings reveal a mechanism by which the decidual microenvironment restrains NK-cell proliferation, promoting immune homeostasis at the maternal-fetal interface.

Microwave ablation (MWA) for large hepatocellular carcinoma (HCC) is frequently compromised by non-uniform thermal distribution and immunosuppressive niche formation. To address these challenges, we engineered an injectable bimodal nanodepot (TCPD) via catalytic crosslinking of dopamine-modified hyaluronic acid by microwave thermal converter cesium-doped Prussian blue, enabling co-delivery of glutaminase 1 inhibitor Telaglenastat and sonosensitizer Chlorin e6. Under combined MWA and ultrasound irradiation, TCPD nanodepot disrupts cellular antioxidant defenses and bioenergetic pathways through glutaminolysis-TCA cycle blockade, metabolically sensitizing large tumors to spatially complementary sono-thermal ablation and enabling complete treatment coverage. This multimodal intervention induces multiple subcellular stresses, including mitochondrial and endoplasmic reticulum dysfunction, genotoxicity, and NAD[+] depletion, which converge to facilitate PANoptosome assembly and immunogenic PANoptosis while activating the cGAS-STING pathway. Subsequent release of damage-associated molecular patterns and immunoregulatory cytokines promotes dendritic cell maturation, M1 macrophage polarization, and T lymphocyte infiltration, ultimately reprogramming the immunosuppressive microenvironment toward an immune‑activated niche. Integration with anti-PD-1 therapy further reinvigorates cytotoxic T lymphocytes and establishes antitumor immune memory to suppress tumor progression and metastasis, offering a multimodal therapeutic strategy for large HCC.