Cellular Immunology[JOURNAL]
Sun
200 papers
Macrophages: Traffic centers in the tumor immune microenvironment.
Zou F, Zhang Y, Wang M … +2 more , Quan Y, Ping H
Cell Immunol · 2025 Dec · PMID 41075580 · Publisher ↗
The tumor microenvironment (TME) has emerged as a prominent focus of cancer research in recent years, with various drugs in this field, including programmed cell death receptor 1 (PD-1) antibodies and cytotoxic T lymphoc...
The tumor microenvironment (TME) has emerged as a prominent focus of cancer research in recent years, with various drugs in this field, including programmed cell death receptor 1 (PD-1) antibodies and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, now included in first-line therapeutic guidelines for cancer. Although macrophages are not as effective as T-lymphocytes in directly killing tumors, they serve as critical mediators in the TME due to their indirect roles in promoting blood vessel formation, facilitating antigen presentation and influencing tumor cell metabolism to affect their infiltration. Macrophages are governed by complex regulatory networks, both independently and as a part of the TME. Extensive research has led to the development of a comprehensive and detailed understanding of these networks and the molecular mechanisms driving macrophage activity. The interactions between macrophages and the TME significantly impact tumor initiation and progression, making macrophages a promising target for cancer therapy. In this review, we discuss recent findings on the factors underlying macrophage polarization in the TME, the critical role of macrophages within the TME, key transcriptional regulators of macrophages, and emerging strategies for targeting macrophages in cancer therapy.
Cgas deficiency promotes tumor growth by supporting B cell persistence and angiogenesis.
Chantawichitwong P, Kumpunya S, Wongtangprasert T … +3 more , Visitchanakun P, Pisitkun T, Pisitkun P
Cell Immunol · 2025 Dec · PMID 41027322 · Publisher ↗
The cGAS sensor activates the STING/IFN signaling pathway, which is crucial for antiviral and antitumor responses. This study aims to investigate the cGAS-mediated immune responses in tumorigenesis using the MC-38 tumor...
The cGAS sensor activates the STING/IFN signaling pathway, which is crucial for antiviral and antitumor responses. This study aims to investigate the cGAS-mediated immune responses in tumorigenesis using the MC-38 tumor model. MC38-tumor models were established in wild-type (WT) and Cgas-deficient mice to investigate immunophenotypes and cellular mechanisms involved in tumor progression. Cgas mice exhibited significantly larger tumors and reduced survival compared to WT mice. Tumors in Cgas mice showed increased fibrosis and neovascularity. WT mice mounted a more robust T-cell-mediated antitumor response, with higher levels of NK and effector T cells, while Cgas mice showed an expansion of B cells, including regulatory B cells producing IL-10. B cells from tumor-bearing Cgas mice demonstrated enhanced survival in the tumor-conditioned medium than those from WT mice. B cell depletion significantly reduced tumor size in WT mice but had minimal effect in Cgas mice, where fibrosis and tumor vasculature persisted. Notably, despite B cell depletion, B cells remained in the tumors of Cgas mice, in contrast to WT mice, where depletion correlated with increased CD8 T cell infiltration. Upregulation of Tgfb1, Tlr7, Tlr9, and Tnfrsf13c in tumors of Cgas mice suggested a tumor microenvironment (TME) that promotes B cell survival. Furthermore, Cgas B cells promoted angiogenesis, as indicated by enhanced endothelial tube formation. cGAS deficiency fosters tumor growth by reducing the antitumor response, promoting a pro-tumor microenvironment, and supporting B cell survival. The Cgas B cells enhance angiogenesis and are resistant to B cell depletion, contributing to tumor progression.
Follicular helper T cells and fibrotic diseases.
Ma Y, Zhou Y, Yu M
Cell Immunol · 2025 Dec · PMID 41015009 · Publisher ↗
T follicular helper (Tfh) cells constitute a functionally specialized subset of CD4+ T lymphocytes that orchestrate germinal center (GC) responses, critically regulating B cell destination and the development of long-ter...
T follicular helper (Tfh) cells constitute a functionally specialized subset of CD4+ T lymphocytes that orchestrate germinal center (GC) responses, critically regulating B cell destination and the development of long-term humoral immunity. Emerging evidence implicates Tfh cells as key mediators in the pathogenesis of multiple fibrotic disorders across multiple organ systems, including systemic sclerosis (SSc), hepatic fibrosis, chronic kidney disease, idiopathic pulmonary fibrosis (IPF) and IgG4-Related Disease (IgG4-RD). This review synthesizes current understanding of Tfh cell biology in fibrosis, aiming to provide deeper insights into their involvement in pathogenesis and identify potential new therapeutic targets.
Exosomes from hypoxic pretreated BMSCs attenuate primary Sjögren's syndrome-induced skin injury via PPARγ-mediated M2-like macrophage activation.
Wang X, Sun X, Yang X … +4 more , Xu G, Wang Y, Jin M, Sun C
Cell Immunol · 2025 Dec · PMID 41005218 · Publisher ↗
BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disorder identified by a triad of sicca symptoms, pain, and fatigue. SS-induced skin injury seriously affects people's health but remains unsolved. Accumulating invest...
BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disorder identified by a triad of sicca symptoms, pain, and fatigue. SS-induced skin injury seriously affects people's health but remains unsolved. Accumulating investigations have confirmed that exosomes (Exos) originating from bone marrow mesenchymal stem cells (BMSCs) can bolster the stressed microenvironment and tissue repair. Present study aimed to unravel therapeutic effects regarding BMSC Exos on SS-induced skin injury. METHODS: In this study, an SS mouse model was constructed, and exosomes from BMSCs (Exos) and hypoxic pretreated BMSCs (HExos) were isolated. The therapeutic effects of exosomes in SS were identified using ELISA, immunohistochemistry, and immunofluorescence. High-throughput sequencing (HTS) was utilized to characterize differentially expressed genes between Exos and HExos. RESULTS: The data showed that Exos, especially HExo treatments, affected the inhibition of SS-induced inflammatory factor expression, cell apoptosis, ROS deposition, and collagen loss. HTS and RT-qPCR detection showed PPARγ functioned importantly for HExo-mediated protective effects against SS-induced skin injury. The in vitro experiment using RAW confirmed that PPARγ expression inhibited LPS-induced M1-like macrophage activation, which was confirmed using the PPARγ antagonist T0070907. PPARγ upregulation improved therapeutic effects regarding Exos upon skin injury in SS mice by promoting M2-like macrophage activation. CONCLUSION: Taken together, our study found that exosomes from hypoxic pretreated BMSCs attenuated primary Sjögren's syndrome-induced skin injury via PPARγ delivery and promoted M2-like macrophage activation.
EGCG remodels the TGF-β cervical cancer micro-environment towards immune responsiveness.
Gnanagurusamy J, Sabanayagam R, Krishnamoorthy S … +2 more , Balasubramanian V, Muthusami S
Cell Immunol · 2025 Dec · PMID 41005217 · Publisher ↗
BACKGROUND: Exploring the role of immune modulators alongside TGF-β in cervical cancer (CC) and PBMCs may improve the understanding of targeted treatment strategies. METHODS: We analyzed expression, overall survival (OS)...
BACKGROUND: Exploring the role of immune modulators alongside TGF-β in cervical cancer (CC) and PBMCs may improve the understanding of targeted treatment strategies. METHODS: We analyzed expression, overall survival (OS), correlation and tumor infiltration of PD-L1, CD55 and CD46, as well as immune cell fractions in CC patients using OncoDB, TIMER 2.0 and TCIA. RT-PCR and western blotting was performed to assess PD-L1, CD55 and CD46 expression. Viability, mitored, apoptosis and MMP-2 were evaluated in CC cells co-cultured with PBMCs. Morphology, crystal violet staining, ROS and MMP-2 were examined in SiHa spheroids. RESULTS: PD-L1 was upregulated, CD55 was significantly increased and CD46 showed no significant difference in HPV16 positive compared with HPV negative individuals. Elevated PD-L1, CD55 and CD46 were associated with reduced OS in HPV16 positive individuals. PD-L1 and CD55 showed moderate positive and negative correlation with TGF-β, respectively, whereas CD46 correlation was negligible. Immune fractions including M1 macrophages (31 %), M2 macrophages (17 %), CD8 T cells (21 %), NK cells (10 %), were linked to reduced OS. TGF-β, PD-L1 and CD46 infiltration were positively corelated with CD8+ T cells. In CC cells, TGF-β stimulation increased PD-L1, while decreasing CD55 and CD46, reducing viability, metabolic activity and inducing apoptosis in HPV (+) co-cultures. EGCG treatment under TGF-β, reduced PD-L1, CD55 and CD46 expression, decreased viability, metabolic activity and MMP-2 secretion, while inducing apoptosis in SiHa co-culture. In 3D spheroids, EGCG inhibited proliferation and MMP-2 activity while increasing ROS production. CONCLUSION: EGCG, by targeting TGF-β and modulating PD-L1 and mCRPs, represents a promising candidate for immunotherapeutic development in CC.
Exploring novel strategies of oncolytic viruses and gut microbiota to enhance CAR-T cell therapy for colorectal cancer.
Yi J, Quji S, Guo L … +3 more , Chai Z, Kong X, Meng J
Cell Immunol · 2025 Nov · PMID 40972447 · Publisher ↗
Colorectal cancer (CRC), ranking as the third most prevalent malignant tumor globally (accounting for 10.0 % of new cancer cases) and the second leading cause of cancer-related deaths (9.4 % of cancer mortality), continu...
Colorectal cancer (CRC), ranking as the third most prevalent malignant tumor globally (accounting for 10.0 % of new cancer cases) and the second leading cause of cancer-related deaths (9.4 % of cancer mortality), continues to escalate in incidence, posing a significant threat to human health. Although conventional therapies such as surgery, radiotherapy, and chemotherapy remain the clinical mainstay, their efficacy in improving patient survival and quality of life has reached a plateau, necessitating the exploration of novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a highly promising approach for cancer treatment. Notably, the complexity of the solid tumor microenvironment (TME) presents challenges for the application of CAR-T therapy in CRC, including antigen heterogeneity, immune suppression, and off-target toxicity. However, the development of multi-target CAR-T cells and their combination with immunomodulatory drugs holds significant clinical potential. Furthermore, in recent years, oncolytic virus (OV) therapy has garnered substantial attention due to its unique antitumor mechanisms. Our study demonstrates that OVs can precisely target CRC tissues, inducing tumor cell apoptosis through selective infection and intracellular replication while concurrently activating systemic antitumor immune responses and inhibiting angiogenesis, thereby achieving multidimensional therapeutic effects. Further investigations reveal that OVs can serve as gene delivery vectors for therapeutic molecules or synergize with chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint inhibitors to significantly enhance treatment efficacy. Simultaneously, gut microbiota, a critical regulator of CRC progression, can influence both CAR-T and OVs therapies through metabolic modulation and immune remodeling. Building upon these mechanisms, this review innovatively proposes a tripartite "OVs-gut microbiota-CAR-T" strategy: OVs may reprogram the immunosuppressive TME and release tumor antigens to enhance CAR-T infiltration and activity, while concurrent modulation of gut microbiota could further alleviate immunosuppression and reduce treatment toxicity, establishing a bidirectional synergistic loop. This interdisciplinary integration strategy may provide a groundbreaking approach to overcome current therapeutic limitations in CRC and advance precision tumor immunotherapy to new frontiers.
Divergent metabolic rewiring shapes altered innate immunity.
Liu M, Wang X, Qu X … +3 more , Wang Y, Shen X, Xu L
Cell Immunol · 2025 Nov · PMID 40926446 · Publisher ↗
Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation...
Both trained immunity (TRIM) and endotoxin tolerance (ET) initiate similar metabolic reprogramming characterized by enhanced glycolysis following an initial stimulus. However, TRIM exhibited heightened immune activation upon restimulation, whereas ET showed suppressed innate immune response. This divergence is attributed to distinct metabolic intermediates accumulated after the initial stimulation. In TRIM, metabolites like fumarate and glutamine derivatives accumulate, reinforcing pro-inflammatory epigenetic modifications. Conversely, ET is characterized by increased itaconate and lactate levels, promoting anti-inflammatory epigenetic changes and metabolic paralysis. This review highlights metabolic intermediates as key regulators of innate immune fate decisions, presenting avenues for targeted immune modulation.
A synergy of CD133 overexpression and TGF-β supplementation in tumorigenesis of ovarian cancer cell lines in a three-dimensional sphere forming model.
Hung HC, Mao TL, Tsui KH … +3 more , Fan MH, Minhalina AP, Liu CL
Cell Immunol · 2025 Nov · PMID 40889488 · Publisher ↗
BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecological malignancy, mainly due to chemoresistance and tumor recurrence. Cancer stem cells (CSCs) may be responsible for chemoresistance, and CSC has become a new t...
BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecological malignancy, mainly due to chemoresistance and tumor recurrence. Cancer stem cells (CSCs) may be responsible for chemoresistance, and CSC has become a new target for treatment. In this study, we aimed to develop a three-dimensional (3D) OC model with well-recapitulated stemness in the tumor microenvironment (TME). RESULTS: We observed that the niche-like environment associated with CSC properties is characterized by the presence of CD133-positive cells during OC sphere induction. The cancer-associated fibroblast (CAF)-integrated 3D multicellular OC model recapitulates enhanced tumorigenicity and cytokine-mediated invasiveness more than the 2D monolayer culture. Chemoresistance of the 3D OC model is also acquired. In addition, the in vivo growth of an established xenograft model with a 3D CAF-integrated OC sphere exhibits proper stemness features and full cancer-associated markers for tumorigenesis. After transduction of the CD133 gene into OC cells, gene ontology (GO) and KEGG pathway enrichment analyses reveal that cytokine-mediated endothelial mesenchymal transition (EMT) is possibly responsible for chemotherapy resistance and tumor progression, and enhanced PAR1, CXCR4, and PD-L1 expressions are also observed. In addition, we found that engineered chimeric antigen receptor (CAR)-T cells targeting PAR1 demonstrated significant in vitro cytotoxicity toward chemoresistant OC sphere with CD133 overexpression. CONCLUSIONS: Taken together, our results show that a CD133-3D OC sphere recaptures TME that mimics a real late-stage OC condition, and it can act as a useful platform with mechanism-verifying in vitro and in vivo experiments in researching OC chemotherapy, immunotherapy, and cell therapy to discover new therapeutic approaches.
Establishment of a multi-parameter flow cytometry method to identify and characterize neutrophil extracellular traps.
Liu W, Ping J, Wu N
Cell Immunol · 2025 Nov · PMID 40858034 · Publisher ↗
Neutrophil extracellular traps (NETs) are web-like decondensed DNA filaments released by activated neutrophils, decorated with antimicrobial proteins such as myeloperoxidase (MPO) and elastase. Although several methods e...
Neutrophil extracellular traps (NETs) are web-like decondensed DNA filaments released by activated neutrophils, decorated with antimicrobial proteins such as myeloperoxidase (MPO) and elastase. Although several methods exist to evaluate NETs formation, including fluorescent microscopy or scanning electron microscopy (SEM), and flow cytometry, each has inherent limitations that restrict widespread application. Given the increasing relevance of NETs in various pathophysiological contexts, we sought to develop a simple, specific, objective and cost-effective flow cytometry-based method to assess NETs both in vitro and in vivo. Our approach leverages multi-parametric flow cytometry to simultaneously evaluate cell size, granularity, DNA decondensation, histone citrullination, and intracellular MPO. This method enables reliable detection of NETs in purified neutrophils as well as in tissue samples. Its performance was validated in parallel with conventional microscopy, confirming specificity and reproducibility. Notably, this FACS-based method is faster, more economical, and free from observer-bias, making it especially well-suited for both research and clinical sample analysis.
Establishing a clinical prediction model of neurosyphilis via a lumbar-puncture-free nomogram.
Wang X, Wang W, Liu Y … +10 more , Wang P, Huang Q, Tian D, Liao Y, Yi Z, Li F, Tang Y, Zhao C, Fan X, Ling Y
Cell Immunol · 2025 · PMID 40834713 · Publisher ↗
OBJECTIVES: Neurosyphilis (NS) can cause a range of central nervous system (CNS) damage, from asymptomatic states to severe mental disorders. While lumbar puncture is a reliable diagnostic method for NS, it is often poor...
OBJECTIVES: Neurosyphilis (NS) can cause a range of central nervous system (CNS) damage, from asymptomatic states to severe mental disorders. While lumbar puncture is a reliable diagnostic method for NS, it is often poorly accepted due to its invasive nature, particularly by patients with mild symptoms. This study aims to develop a prediction model for the early diagnosis of NS that without requiring lumbar puncture. METHODS: Clinical data, including imaging, routine blood tests, immune markers, HIV status and cerebrospinal fluid (CSF) examination, were collected from the Shanghai Public Health Clinical Center from 2021 to 2023,. The dataset was randomly split into training and validation sets in an 8:2 ratio. Univariate analysis, the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to identify significant predictors. RESULTS: Out of 1078 suspected patients, 702 confirmed syphilis patients with positive Treponema pallidum specific antibody (anti-TP) and positive Treponema Pallidum Particle Agglutination (TRUST) in serum were selected. Among them, 246 patients were diagnosed as NS based on the positive anti-TP in CSF, while 456 patients were classified as non-neurosyphilis (NNS). In the NS group, cerebral ischemia/infarction, ataxia, decreased vision, mental/behavioral disorders, memory impairment, high levels of anti-TP and TRUST (>1:16), elevated red blood cell (RBC) and platelet (PLT) counts, and shorter prothrombin time (PT) were identified. A nomogram was established based on independent prognostic factors. The receiver operating characteristic (ROC) curves and calibration curves showed high predictive accuracy, and clinical decision curve analysis (DCA) indicated good clinical applicability. CONCLUSIONS: The developed nomogram offers a reliable and non-invasive method for early identification of NS in syphilis patients, regardless of their HIV or immune status.
ANAPC5 mitigates acute lung injury through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis.
Wang Y, Zhang X, Zhang J … +5 more , Zhao M, Chong Y, Gu Q, Meng X, Zhao M
Cell Immunol · 2025 · PMID 40834712 · Publisher ↗
Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately lead...
Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately leads to pulmonary dysfunction. ANAPC5 (Anaphase-promoting complex subunit 5) is an E3 ubiquitin ligase known for its anti-inflammatory properties. This study aims to investigate the effects of ANAPC5 on ALI and its underlying molecular mechanism. In the lung tissue of an ALI mouse model induced by lipopolysaccharide (LPS) administration, we observed downregulation of ANAPC5. Through both in vivo and in vitro experiments, we assessed the effect of ANAPC5 on lung injury by conducting pathological analysis and molecular biological detection. ANAPC5 overexpression alleviated inflammatory cell infiltration, reduced alveolar wall thickening, suppressed pulmonary inflammation, and decreased the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue of the ALI model. Moreover, ANAPC5 inhibited M1 polarization and promoted M2 polarization of macrophages both in vitro and in vivo. We also found that ANAPC5 significantly suppressed the activation and expression of the epidermal growth factor receptor (EGFR) through inducing its ubiquitination in macrophages. In LPS-induced M1 macrophages, the presence of EGFR significantly decreased CD24 expression, followed by reversing the inhibitory effects of ANAPC5 on inflammatory responses and macrophage polarization. Collectively, our findings suggest that ANAPC5 serves as a therapeutic molecular target that mitigates ALI through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis.
METTL3 positively regulates the development and cytotoxicity of human embryonic stem cells-derived NK cells.
Yin X, Zhang Z, Qiu J … +14 more , Gong Y, Bi Q, Meng M, Lai Q, Wang H, Zhou S, Gao Y, Zhang L, Wu W, Song L, Wang J, Wang F, Zhong Z, Deng Y
Cell Immunol · 2025 · PMID 40779962 · Publisher ↗
Human embryonic stem cell-derived NK (hESC-NK) cells or induced pluripotent stem cell derived NK cells have demonstrated efficacy and safety in clinical trials for cancer therapy and serve as a valuable tool for studying...
Human embryonic stem cell-derived NK (hESC-NK) cells or induced pluripotent stem cell derived NK cells have demonstrated efficacy and safety in clinical trials for cancer therapy and serve as a valuable tool for studying the mechanisms of human NK cell development and effector functions. We previously demonstrated that the methylase METTL3 was essential for the development and effector functions of murine NK cells, but its role in human NK cells remained unknown. Herein, we constructed an H1 ESC strain with reduced METTL3 expression using lentivirus-delivered short hairpin (sh) RNA and generated hESC-NK cells via a two-stage differentiation system. Our findings demonstrated that METTL3 knockdown in hESCs reduced the proportion of hematopoietic stem and progenitor cells (HSPCs, CD34 cells) during embryoid bodies (EBs) formation, and impaired subsequent differentiation into mature NK cells. Moreover, ESC-NK cells derived from shMETTL3-ESC (called shMETTL3-ESC-NK) showed impaired anti-tumor activity, evidenced by downregulation of mRNA and protein levels of critical effectors (perforin, granzyme B and IFN-γ) and reduced cytotoxicity against target cells. Furthermore, both mRNA and protein levels of T-BET and EOMES were significantly down-regulated in shMETTL3-ESC-NK cells. These transcription factors are critical for NK cell development and cytotoxicity, and their downregulation may underlie the maturation defects of shMETTL3-ESC-NK cells. Collectively, our study elucidates that METTL3 promotes the development, maturation and cytotoxicity of hESC-NK cells, recapitulating previous reports in murine NK cells.
Identification of Epstein-Barr virus nuclear antigen 1 (EBNA1)-specific T-cell receptors: implications for immunotherapy targeting EBV-associated malignancies.
Liu Y, Pan Y, Ding H … +5 more , He W, Chen H, Hu Z, Lu Z, Ke Y
Cell Immunol · 2025 · PMID 40753940 · Publisher ↗
BACKGROUND: Epstein-Barr virus nuclear antigen (EBNA1) is uniquely expressed across all three EBV latency types, making it an ideal target for TCR-engineered T-cell therapy against EBV-associated malignancies. However, p...
BACKGROUND: Epstein-Barr virus nuclear antigen (EBNA1) is uniquely expressed across all three EBV latency types, making it an ideal target for TCR-engineered T-cell therapy against EBV-associated malignancies. However, preparation of EBNA1-specific TCR-T cells, particularly for EBV latency I type, remains exploratory. METHODS: EBNA1-specific T cells were stimulated using autologous dendritic cells (DCs) pulsed with peptides synthesized from the complete sequence (except the glycine-alanine repeat region) of the EBNA1 of EBV strain B95-8. For pre-stimulated and post-stimulated T cells, candidate EBNA1-specific TCRs with significantly increased frequencies were identified using high-throughput single-cell TCR V(D) J sequencing. The functionality of EBNA1-specific TCR-engineered T cells was assessed in vitro against lymphoblastoid cell lines (LCLs) and EBNA1 peptide-pulsed DCs. RESULTS: EBNA1-specific T cells were successfully expanded. Candidate EBNA1-specific TCRs were isolated, corresponding TCR gene sequences were constructed and introduced into peripheral blood T cells. Engineered T cells expressing EBNA1-specific TCR demonstrated specific recognition of EBNA1 presented by autologous LCLs and DCs in vitro. CONCLUSIONS: This study establishes the feasibility of expanding functional EBNA1-specific TCR-T cells, providing a foundation for adoptive cell therapy targeting all EBV-associated malignancies, including latency I.
Chloroquine treatment ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell differentiation and pDC accumulation.
Li Y, Shao Y, Ma X … +10 more , Li Y, Yang Y, Wang F, Yan Y, Hu X, Dai Y, Li M, Löhning M, Shen P, Lin J
Cell Immunol · 2025 · PMID 40701030 · Publisher ↗
OBJECTIVES: Chloroquine (CQ) has been used to treat rheumatoid arthritis and systemic lupus erythematosus, but its use in multiple sclerosis (MS) is limited by side effects and insufficient efficacy. To enhance treatment...
OBJECTIVES: Chloroquine (CQ) has been used to treat rheumatoid arthritis and systemic lupus erythematosus, but its use in multiple sclerosis (MS) is limited by side effects and insufficient efficacy. To enhance treatment outcomes, understanding CQ's therapeutic mechanisms in MS is crucial. Thus, we administered CQ to mice with experimental autoimmune encephalomyelitis (EAE) and investigated its disease-ameliorating effects and underlying cellular mechanisms. METHODS: CQ was applied intraperitoneally six days after EAE induction, immune responses, with a focus on inflammatory and regulatory T cells, as well as dendritic cells in blood, lymph nodes, spleen, and bone marrow were analyzed by flow cytometry. RESULTS: CQ treatment significantly reduced cumulative disease score and maximal disease score in CQ-treated group. Immunohistochemical analysis of the spinal cords confirmed the reduced demyelination after CQ treatment, which is accompanied by significantly decreased infiltration of T cells, B cells, and macrophages, and less activated microglia cells. Flow cytometry analysis of peripheral lymphoid organs revealed a significant decrease of inflammatory Th17 cells, which is associated with reduced pDC and their IFN-α expression, as well as Treg cells in CQ-treated mice. Indeed, depletion of pDC alone or simultaneously with CQ treatment significantly reduced EAE severity. CONCLUSION: Our results demonstrated that CQ treatment inhibits the development of EAE disease on one hand by enhancing the expansion of Treg in dLN and spleen, and on the other hand by inhibiting the accumulation of pDC and their IFN-α expression in the spleen and bone marrow. This joint effort restricts the level of inflammation in peripheral and later in CNS. Furthermore, developing a pDC-targeted CQ treatment will not only increase the treatment efficiency, but also largely decrease side effects.
Sfrp2-deficient colonic fibroblasts drive mucosal inflammation and epithelial injury in ulcerative colitis.
Zhu M, Diao Z, Hu L … +1 more , Fan Z
Cell Immunol · 2025 · PMID 40680407 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory disorder targeting the colon, which remains clinically challenging due to limited targeted therapies. Although intestinal fibroblasts have emerged as critical regulators...
Ulcerative colitis (UC) is a chronic inflammatory disorder targeting the colon, which remains clinically challenging due to limited targeted therapies. Although intestinal fibroblasts have emerged as critical regulators of mucosal immunity and tissue repair, their molecular mechanisms in UC pathogenesis are poorly defined. Here, we investigate the functional role of secreted frizzled-related protein 2 (SFRP2, a Wnt signaling modulator) knockdown fibroblasts in immune homeostasis and the severity of UC using Sfrp2; Col1a2-Cre mice (fibroblast-specific knockout). In the dextran sulfate sodium (DSS)-induced colitis model, we found SFRP2 in fibroblasts have negative correlation with the severity of UC. That Sfrp2 CKO mice exhibited exacerbated colitis symptoms and accelerated inflammatory progression, and showed increased ratio of Th17 cells and decreased ratio of Treg cells. These findings revealed that Sfrp2 in fibroblasts plays a crucial role in protecting against inflammatory responses and T-cell immune dysregulation. Therefore, Sfrp2 may serve as a potential therapeutic target for UC treatment.
Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor.
Yan K, Xiao Z
Cell Immunol · 2025 · PMID 40664123 · Publisher ↗
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor mi...
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1-dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1-mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
Tiggeler A, Coffer PJ
Cell Immunol · 2025 Aug · PMID 40618715 · Publisher ↗
Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and...
Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.
Functional avidity enhancement of a T-cell receptor targeting the KRAS cancer neoantigen.
Luo F, Yao Q, Hao Y … +6 more , Shen M, Chen T, Wu R, Li T, Han X, Jin A
Cell Immunol · 2025 Aug · PMID 40582295 · Publisher ↗
Engineered T cell receptors (TCRs) targeting neoantigens represent a transformative approach in cancer immunotherapy, yet their clinical potential is limited by low natural TCR avidity and the risk of off-target toxicity...
Engineered T cell receptors (TCRs) targeting neoantigens represent a transformative approach in cancer immunotherapy, yet their clinical potential is limited by low natural TCR avidity and the risk of off-target toxicity from over-engineered TCRs with excessive high-affinity. Here, we developed a TCR engineering platform to enhance the functional avidity of a TCR targeting the KRAS G12D mutation (KRAS) while avoiding reactivity to the wild-type (WT) peptide. We separately constructed CDR3α- and CDR3β-focused TCR libraries derived from an HLA-A*11:01-restricted KRAS-specific TCR and screened them using alternating positive and negative selection: KRAS-pulsed antigen-presenting cells (APCs) drove functional avidity, while KRAS-pulsed APCs eliminated cross-reactive clones. From these libraries, we identified CDR3α variants with modest avidity gains and reduced off-target reactivity, and CDR3β variants with significant avidity enhancement and potent tumor cytotoxicity, albeit with variable cross-reactivity profiles. This strategy enables precision engineering of neoantigen-specific TCRs, balancing therapeutic efficacy and safety for adoptive transfer TCR-T therapy.
M6A methyltransferase ZC3H13-mediated downregulation of GPX4 mRNA stability inhibits the progression of kidney renal clear cell carcinoma (KIRC).
Ruan D, Huang R, Wang H … +3 more , Liu K, Huang Y, Li Z
Cell Immunol · 2025 Aug · PMID 40578066 · Publisher ↗
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is one of the fatal genitourinary diseases and accounts for most malignant kidney tumors. Previous studies have indicated that RNA modification N6-methyladenosine zinc...
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is one of the fatal genitourinary diseases and accounts for most malignant kidney tumors. Previous studies have indicated that RNA modification N6-methyladenosine zinc-finger CCCH-type containing 13 (ZC3H13) plays a vital regulatory role in KIRC. However, the biological role and mechanism of ZC3H13 in KIRC are poorly defined. METHODS: TIMER, ENCORI, and UALCAN databases were used to analyze the expression feature and prognostic significance of ZC3H13. ZC3H13 and Glutathione Peroxidase 4 (GPX4) mRNA level and protein level were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell proliferation and apoptosis were measured using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry. A xenograft model analyzed the effects of ZC3H13 on tumor growth in vivo. Superoxide dismutase (SOD) activity, Glutathione (GSH) level, and Reactive oxygen species (ROS) were determined using special assay kits. Adenosine triphosphate (ATP) level was detected using kit. Mitochondrial membrane potential changes were analyzed using flow cytometry. RESULTS: ZC3H13 was decreased, and GPX4 was increased in KIRC tissues and cells. Moreover, overexpressing ZC3H13 hindered KIRC cell proliferation, promoted apoptosis, oxidative stress, and disrupted mitochondrial function in vitro, as well as blocked tumor growth in vivo. At the molecular level, ZC3H13 could decrease the stability and expression of GPX4 mRNA via m6A methylation. CONCLUSION: ZC3H13 destabilizes GPX4 mRNA in an m6A-dependent manner, thereby repressing KIRC cell proliferation, expediting apoptosis, oxidative stress, and impairing mitochondrial function, which provided a promising therapeutic target for KIRC.
Quercetin alleviates diabetic nephropathy by inhibiting M1 macrophage polarization via targeting NLRC5/NLRP3 pathway.
Abudoureyimu A, Chen C, Hu Y … +2 more , Nuermaimaiti D, Liu T
Cell Immunol · 2025 Aug · PMID 40570646 · Publisher ↗
BACKGROUND: The activation imbalance of M1/M2 macrophage phenotypes is crucial in diabetic nephropathy (DN). This study aimed to explore the molecular mechanisms underlying quercetin's action against DN. METHODS: In vitr...
BACKGROUND: The activation imbalance of M1/M2 macrophage phenotypes is crucial in diabetic nephropathy (DN). This study aimed to explore the molecular mechanisms underlying quercetin's action against DN. METHODS: In vitro, RAW 264.7 macrophages were incubated with high glucose (HG) with or without quercetin. Overexpression of NLRC5 was investigated to elucidate the mechanism. M1/M2 macrophage differentiation was assessed by flow cytometry using cell surface markers CD86 and CD206. In vivo, a DN mouse model was created using a high-fat diet and streptozotocin (STZ). Quercetin was administered intragastrically to DN mice at 50 mg/kg and 100 mg/kg. After euthanasia, mouse kidneys were analyzed by hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemistry (IHC) staining. ELISA assay and western blot analysis were performed to determine related molecular levels. RESULTS: In vitro, quercetin significantly reduced HG-induced expressions of CD86, iNOS, NLRC5, NLRP3, and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), while increasing HG-induced CD206, Arg-1, and IL-10 in RAW 264.7 macrophages. However, these effects of quercetin were abolished when NLRC5 was overexpressed. In DN mice, quercetin administration ameliorated renal histopathological injury and fibrosis. Notably, there was a significant reduction in expressions of NLRC5, NLRP3, Col1a1, and α-SMA, along with decreased expressions of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). CONCLUSION: This study showed that quercetin improves DN by inhibiting M1-type macrophages through targeting the NLRC5/NLRP3 pathway.
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