The discovery of broadly neutralizing antibodies (bNAbs) that target conserved epitopes on the HIV-1 envelope glycoprotein (Env) has garnered significant attention for its potential in the development of effective therapeutic and vaccine strategies. In this study, we isolated and characterized a CD4 binding site (CD4bs) antibody, FD22, from an elite neutralizer in China who had been infected with a clade B virus through contaminated blood plasma for 23 years. The heavy chain of FD22 was derived from a rarely reported IGHV3-30 germline gene and exhibited an exceptionally high degree of somatic hypermutation (SHM) (37%), along with a long and unique CDRH3 loop of 20-amino acids. FD22 exhibited potent and broad neutralizing activity, comparable to that of the well-known bNAb VRC01. It effectively neutralized 82% of a panel of 145 diverse HIV-1 pseudoviruses, including the two major circulating strains in China, CRF01_AE and CRF07_BC. FD22 bound strongly to HIV-1-infected cell lines, efficiently engaged FcγRIIIa receptors, triggered NK cell degranulation and the release of key cytokines such as IFN-γ and β-chemokines, and robustly induced antibody-dependent cellular cytotoxicity (ADCC) against HIV-1-infected target cells. Structural prediction for FD22 and the HIV Env SOSIP trimer performed by AlphaFold3, site-mutagenesis, and autologous virus reverse mutation assays revealed that the epitope of FD22 spans key CD4 binding site, including Loop D, the CD4 binding loop (CD4 BLP), and the V5 Loop. The unique long CDRH3 loop of FD22 interacts with the CD4 binding site through its negatively charged residue R102, distinguishing it from other CD4bs antibodies. Our findings provide valuable insights into the mechanisms of FD22 in viral neutralization and ADCC. The dual functionality of FD22 enhances its potential as a promising therapeutic antibody and offers new avenues for designing CD4bs-targeting vaccines with enhanced ADCC capabilities.
© 2025. The Author(s).

The use of electronic (e)-cigarettes in the long term has been associated with an increased risk of respiratory diseases. Dual use of e-cigarettes and traditional cigarettes may increase these risks even more due to the combined exposure effects of these products. The aim of this study was to investigate the local and systemic effects of e-cigarette use for more than one year and compare them with healthy non-smokers, cigarette smokers, and dual users.
The clinical study was conducted among 22 healthy non-smokers, 20 e-cigarette users, 20 cigarette smokers, and 20 dual users. Participants were matched with age and BMI, had normal baseline lung function, and had no allergies. Exhaled FeNO and bronchial responsiveness were assessed along with reactive oxygen species (ROS), toll-like receptor (TLR) expression, and inflammatory cytokines in blood and sputum.
Exhaled FeNO was higher in e-cigarette users (14 ppb, p = 0.04) and lower in cigarette smokers (9 ppb, p = 0.04) compared to healthy non-smokers (11 ppb). Bronchial responsiveness was increased in e-cigarette users (1.9 mg, p = 0.01) and cigarette smokers (1.9 mg, p = 0.01) compared to healthy non-smokers (2.9 mg). ROS in blood and sputum in e-cigarette users (p = 0.005 and p = 0.04) and dual users (p = 0.003 and p = 0.04) were increased. Also, TLR2 expression in blood granulocytes in all exposed groups (p = 0.001), TLR2 and TLR4 expression in sputum in e-cigarette users (p = 0.04 and p = 0.03) and dual users (p < 0.0001 and p = 0.004) were increased. Moreover, the percentage of IL13 and IFNγ cytokine-producing T cells in blood were increased in e-cigarette users (p = 0.0001 and p < 0.0001) and dual users (p = 0.001 and p < 0.0001).
Our research indicates that both local and systemic inflammatory responses, along with innate immune receptor activity, were significantly altered in e-cigarette users and dual users. Notably, these alterations were detected in e-cigarette users within a short timeframe of just 1 to 3 years of use.
Not applicable.
© 2025. The Author(s).

B7 homolog 3 (B7-H3), an overexpressed antigen across multiple solid cancers, represents a promising target for CAR T cell therapy. This study investigated the expression of B7-H3 across various solid tumors and developed novel monoclonal antibodies (mAbs) targeting B7-H3 for CAR T cell therapy.
Expression of B7-H3 across various solid tumors was evaluated using RNA-seq data from TCGA, TARGET, and GTEx datasets and by flow cytometry staining. B7-H3-specific mAbs were developed by immunizing mice with human B7-H3, screening with ELISA, and analyzing kinetics with surface plasmon resonance. These mAbs were used to create second-generation CAR constructs, which were evaluated in vitro and in vivo for their antitumor function.
We identified four mAb clones from immunized mice, with three demonstrating high specificity and affinity. The second-generation B7-H3 CAR T cells derived from these mAbs exhibited robust cytotoxicity against B7-H3-positive targets and successfully infiltrated and eliminated tumor spheroids in vitro. In a xenograft mouse model of glioblastoma, these CAR T cells, particularly those derived from clone A2H4, eradicated the primary tumor, and effectively controlled rechallenge tumor, resulting in prolonged survival of the xenograft mice. In vivo T cell trafficking revealed high accumulation and persistence of A2H4-derived CAR T cells at the tumor site.
Our results provide novel B7-H3-targeted CAR T cells with high efficacy, paving the way for clinical translation of solid tumor treatment.
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson's disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function.
© 2024, Jin, Xing, Dai et al.

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1+-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-β, secreted by tumor-infiltrated CCR1+-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis. Hereby, we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules (C/T-NVs) to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding. Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis. C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs. Collectively, C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC. In further exploration, high expression of programmed cell death ligand-1 (PD-L1) is observed in clinical specimens of SMAD4-deficient CRC. Combining C/T-NVs with anti-PD-L1 antibody (aPD-L1) induces tertiary lymphoid structure formation with sustained activation of CTLs, CXCL13+-CD4+ T, CXCR5+-CD20+ B cells, and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors, thus eradicating metastatic foci. Our strategy elicits pleiotropic antimetastatic immunity, paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.
© 2024 The Authors.