Chimeric antigen receptor (CAR)-T cell immunotherapy shows significant success in hematologic malignancies. However, it faces critical challenges in solid tumours, such as suppressive tumour microenvironment (TME) and an...Chimeric antigen receptor (CAR)-T cell immunotherapy shows significant success in hematologic malignancies. However, it faces critical challenges in solid tumours, such as suppressive tumour microenvironment (TME) and antigenic heterogeneity, highlighting the urgent need for effective and safe CAR products. The integration of artificial intelligence (AI) into CAR-T cell immunotherapy offers exceptional opportunities to improve its therapeutic efficacy. More specifically, this paper highlights the transformative role of AI in addressing key challenges that impede the success of CAR-T cell therapy in solid tumours, including assisting in CAR design and manufacturing process, identifying novel CAR-targeted genes, and detecting cell heterogeneity in solid tumours. We remain optimistic about AI-driven strategies for enhancing CAR T-cell persistence, trafficking, and visualisation in the TME. In addition, we highlight the current challenges and prospects for advancing AI-driven CAR-T cell therapies.
Ahmadipanah S, Shariat Rad P, Montaseri M
… +3 more, Nemati H, Sadeghi M, Ramezani M
BMC Immunol
· 2026 Feb · PMID 41709148
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BACKGROUND: Psoriasis is an immune-mediated inflammatory disease with a strong genetic basis. The Interleukin-23 (IL-23)/Th17 axis is central to its pathogenesis. While IL-23 is established, studies on systemic serum lev...BACKGROUND: Psoriasis is an immune-mediated inflammatory disease with a strong genetic basis. The Interleukin-23 (IL-23)/Th17 axis is central to its pathogenesis. While IL-23 is established, studies on systemic serum levels and IL23R gene polymorphisms yielded varied results. Our study clarified these associations through a systematic review and meta-analysis. METHODS: A systematic search was performed to find relevant studies. For serum IL-23, a random-effects model calculated overall Hedges’s g. For polymorphisms, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for allelic, dominant, and recessive models. Heterogeneity (I² statistic) and sensitivity analyses were performed. RESULTS: Meta-analysis of serum IL-23 levels (six studies) showed no significant difference between patients and controls (Hedges’s g = -0.48, 95% CI: -1.58 to 0.62) with high heterogeneity (I² = 96.34%). For polymorphisms, the rs11209026 A allele showed a significant protective effect (OR = 0.52, p = 0.002). Conversely, rs2201841 increased psoriasis risk (OR = 1.39, p = 0.001), as did rs7530511 under the recessive model (OR = 1.29, p = 0.014). Significant associations were found between polymorphisms and both psoriasis severity (p < 0.001) and clinical type (p < 0.001). CONCLUSION: Our meta-analysis confirms a significant association between IL23R polymorphisms and susceptibility to psoriasis, with rs11209026 being protective and rs2201841 conferring risk. However, data does not support serum IL-23 as a reliable biomarker. This study widens the view toward personalized medicine and using polymorphisms as prognostic models.
Kwon DI, Bhagchandani SH, Ehrenzeller SA
… +1 more, Iwasaki A
Nat Rev Immunol
· 2026 Jul · PMID 41699393
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Mucosal surfaces are primary entry sites for many infectious pathogens, yet parenteral vaccination alone often fails to elicit effective mucosal immunity. Mucosally delivered vaccines offer a promising strategy for reinf...Mucosal surfaces are primary entry sites for many infectious pathogens, yet parenteral vaccination alone often fails to elicit effective mucosal immunity. Mucosally delivered vaccines offer a promising strategy for reinforcing frontline defences and inducing localized, pathogen-specific immune responses. Recent studies indicate that mucosal vaccines elicit tissue-resident memory T and B cells, along with robust local antibody secretion, to prevent infection and transmission. However, achieving sterilizing immunity at mucosal sites proves challenging owing to the complex immune environments consisting of epithelial barriers, varying mucus composition, pH differences and hormonal influences. In this Review, we outline how specialized immune-inductive and effector mechanisms across distinct mucosal compartments contribute to protective immunity and discuss emerging strategies to harness multilayered mucosal immunity to develop safe, effective vaccines that elicit durable protection.
Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals...Older individuals exhibit distinct biochemical and functional changes in their immune cells that can lead to chronic inflammation, reduced immunity to pathogens and organ dysfunction. Immune cells from older individuals acquire dysfunctional immunosenescent phenotypes that are classified as inflammatory, exhausted or senescent. Key molecular mechanisms, commonly described as hallmarks of ageing, drive the development of these phenotypes through both cell-autonomous and non-autonomous mechanisms. Importantly, the ageing immune system can drive multi-organ dysfunction and systemic ageing, suggesting that improving immune function in older individuals could have significant health benefits. Here, we review the effects of ageing on various immune cell subsets in mice and humans. We describe the molecular mechanisms that drive these functional changes and their effects on both lymphoid and non-lymphoid organs. We also discuss therapeutic approaches to improve the function of the ageing immune system to increase resilience and extend healthspan.
Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fi...Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fibrosis being one of the most common and life-threatening forms. Despite marked research efforts, effective antifibrotic therapies remain limited, largely due to an incomplete understanding of the underlying disease mechanisms. At the centre of fibrotic processes are fibroblasts, which are tissue-resident mesenchymal cells responsible for extracellular matrix production, tissue remodelling, wound healing and fibrosis. For decades, the biology of fibroblasts remained poorly understood, but advances in single-cell sequencing have recently provided deeper insights into their heterogeneity, plasticity and functional diversity. These insights have prompted renewed efforts to identify the core regulatory programmes that govern fibroblast states in health and disease. In this Review, we examine how immunological, mechanical and metabolic regulators influence fibroblast function in fibrosing interstitial lung diseases. We show how loss of stromal regulation through chronic inflammation, immune dysfunction, altered tissue biomechanics and metabolic stress can tip the balance from successful tissue repair to progressive fibrosis.
Gerek ME, Tekinalp A, Çölkesen F
… +5 more, Önalan T, Akkuş FA, Kılınç M, Kahraman S, Arslan Ş
BMC Immunol
· 2026 Feb · PMID 41673825
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BACKGROUND: Alterations in immunoglobulin levels are commonly observed in hematologic malignancies and immune-mediated cytopenias, reflecting underlying immune dysregulation. While the prognostic relevance of hypogammagl...BACKGROUND: Alterations in immunoglobulin levels are commonly observed in hematologic malignancies and immune-mediated cytopenias, reflecting underlying immune dysregulation. While the prognostic relevance of hypogammaglobulinemia (HGG) has been studied in chronic lymphocytic leukemia (CLL), comparable data across a broader range of hematologic diagnoses remain limited. This study aimed to conduct a comparative analysis of baseline immunoglobulin profiles (IgG, IgA, IgM, IgE) across a heterogeneous cohort of patients with NHL, CLL, HL, ITP, and AIHA. Our primary objective was to evaluate the disease-specific associations of these profiles with survival outcomes to identify diagnostic groups that benefit most from baseline immune profiling. RESULTS: A total of 779 patients were included: 294 with NHL, 220 with CLL, 106 with HL, 128 with ITP, and 31 with AIHA. Quantitative and categorical analyses demonstrated significant differences in immunoglobulin levels across disease groups. CLL patients exhibited the highest frequency of low immunoglobulin levels, particularly for IgM and IgA. Kaplan–Meier analysis revealed numerically shorter overall survival in patients with low pretreatment IgG levels, although this difference was not statistically significant in the pooled heterogeneous cohort (p = 0.119). However, this association was not confirmed in the overall multivariable Cox regression model. Subgroup analysis using diagnosis-specific Cox models identified normal/high IgG status as independently associated with improved survival in NHL (HR: 0.543; p = 0.017), but not in CLL, HL, ITP, or AIHA. Associations for IgA, IgM, and IgE with mortality were not evaluated in these diagnosis-specific models. CONCLUSIONS: While low pretreatment IgG levels were associated with poorer survival in the overall cohort on univariate analysis, this association was not significant in the multivariable model. However, subgroup analysis identified low IgG as an independent and significant predictor of mortality in patients with NHL, but not in other diagnoses. These findings highlight that the prognostic value of immunoglobulin profiling is highly disease-specific. Baseline IgG assessment appears most relevant for risk stratification in NHL. However, the use of all-cause mortality limits our ability to discern the specific mechanism (e.g., infection-related vs. disease-progression-related) underlying this association.
Yang Y, Zhang D, Xu Z
… +9 more, Wang C, Wu R, Ma S, Yuan Y, Sun Y, Qian J, Jiang X, Ma C, Chen M
BMC Immunol
· 2026 Feb · PMID 41667967
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BACKGROUND: Sepsis induces systemic inflammation and multi-organ dysfunction, with the lungs frequently affected. Elevated in endothelial cells under hypoxic and inflammatory stressors, NDRG1's contribution to septic pul...BACKGROUND: Sepsis induces systemic inflammation and multi-organ dysfunction, with the lungs frequently affected. Elevated in endothelial cells under hypoxic and inflammatory stressors, NDRG1's contribution to septic pulmonary pathology remains largely uncharacterized. This study investigates whether NDRG1 exacerbates pulmonary inflammation through PKM2-dependent STAT3/NF-κB signaling. METHODS: Mice underwent cecal ligation and perforation to model sepsis, with lung morphology examined by H&E staining. Transcriptional levels of VE-cadherin, ICAM-1, VCAM-1, and cytokines TNF-α, IL-6, and IL-1β were assessed by qPCR, while STAT3/NF-κB phosphorylation was determined by Western blot. NDRG1 localization in pulmonary endothelial cells was evaluated by immunofluorescence, and the NDRG1-PKM2-STAT3/NF-κB axis was further examined using Ndrg1 < sup>-/-</sup> mice and PKM2 modulators (shikonin; TEPP-46). RESULTS: CLP-induced sepsis caused severe pulmonary hemorrhage, edema, and alveolar destruction, accompanied by increased ICAM-1, VCAM-1, and proinflammatory cytokines, as well as reduced VE-cadherin expression. NDRG1 was markedly upregulated in septic endothelia, while its deletion alleviated lung injury, inflammation, and cytokine release by inhibiting PKM2-dependent STAT3/NF-κB phosphorylation. PKM2 inhibition with shikonin reproduced, whereas activation with TEPP-46 abolished, these protective effects, confirming the NDRG1-PKM2-STAT3/NF-κB axis as a pivotal regulator of sepsis-induced pulmonary inflammation. CONCLUSION: By orchestrating downstream STAT3 and NF-κB signaling cascades through PKM2 dependency, NDRG1 contributes to the progression of septic lung injury via increased inflammatory responses and disruption of endothelial integrity. Intervening in this signaling route may offer a viable avenue for therapeutic management of lung injury linked to sepsis.
Age-related alterations in the immune system-collectively known as immunosenescence-include both quantitative and qualitative changes across various immune cell populations, including B cells, natural killer cells and T...Age-related alterations in the immune system-collectively known as immunosenescence-include both quantitative and qualitative changes across various immune cell populations, including B cells, natural killer cells and T lymphocytes, affecting their structure, phenotype and function. While these changes have been characterised biochemically and physiologically, their biophysical manifestations remain less understood, particularly in individuals that achieve exceptional longevity. Here, we investigate the mechanical and structural properties of memory CD4 T cells from mice across three aging stages: old (72 ± 4 weeks), very old (96 ± 4 weeks) and long-lived (> 120 weeks). We conducted a cross-sectional analysis combining micropipette aspiration, 3D confocal microscopy, spontaneous migration assays and flow cytometry to evaluate cellular stiffness, motility, nuclear morphology and cytoskeletal organisation. Our results confirm previous reports of increased stiffness and reduced migration in T cells from very old mice. However, this trend does not persist in long-lived individuals, who display mechanical and migratory properties similar to younger cohorts. Relative nuclear size (R /R ) and actin organisation also stabilise in this group, suggesting the maintenance of intracellular architecture despite advanced chronological age. Notably, no significant changes were found in the expression levels or distribution of key structural proteins (actin, myosin, vimentin), nor in markers of DNA methylation (5-mC) or cellular senescence (p16). These findings support the concept of mechanical resilience in the immune system as a feature of successful aging, highlighting that certain biophysical traits may be preserved or selectively maintained in extreme longevity. This study provides novel evidence linking T cell mechanics with immune health and longevity and identifies candidate parameters for future investigations into aging biomarkers.
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the pathogen's ability to evade host immune responses and persist within macrophages. We investigated the met...Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a significant global health challenge due to the pathogen's ability to evade host immune responses and persist within macrophages. We investigated the metabolic changes in mouse bone marrow-derived macrophages (BMDMs) upon Mtb infection and identified significant alterations in gene expression related to key metabolic pathways through RNA sequencing analyses. Among them, glycolysis-related genes, including hypoxia-inducible factor 1α as a key regulator of glycolysis, are upregulated in Mtb-infected BMDMs. To investigate whether glycolysis plays a critical role in reducing intracellular Mtb growth, we cultured Mtb-infected BMDMs under high- or low-glucose conditions. We found that high-glucose conditions increased glycolytic enzyme levels, inducible nitric oxide synthase expression and proinflammatory cytokine production, reducing Mtb's intracellular survival. HIF1α agonist treatment increased glycolysis, reactive oxygen species levels and proinflammatory cytokine production, enhancing bactericidal activity against Mtb. In contrast, inhibition of HIF1α by a specific inhibitor FM19G11 leads to decreased glycolysis, reduced proinflammatory cytokine production and increased Mtb survival. Since succinate has been known to increase the stabilisation and activation of HIF1α, we added succinate to Mtb-infected BMDMs to evaluate the function of succinate related to HIF1α activation. As expected, succinate treatment enhanced glycolysis through HIF1α stabilisation and shifted BMDMs to proinflammatory M1-like phenotype. Our findings indicate that Mtb-induced glycolysis plays a central role in the reduction of intracellular Mtb in BMDMs. Succinate is a key factor for HIF1α-mediated glycolysis in Mtb-infected BMDMs.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus associated with severe hemorrhagic fever and high mortality in humans. The genome is comprised of three segments of single-stranded, negative-...Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne orthonairovirus associated with severe hemorrhagic fever and high mortality in humans. The genome is comprised of three segments of single-stranded, negative-sense RNA. The nucleocapsid (NP) protein, which is the focus of our study, encoded by the smallest (S) segment, plays a central role in viral RNA encapsidation and is known to be highly immunogenic, eliciting innate, humoral and cellular immune responses. This study aimed to identify the immunodominant regions of the NP that trigger T cell-mediated immune responses. To this end, three truncated variants of the NP from the CCHFV Kelkit'06 strain [NPdelN(1-135 aa), NPdelM(136-295 aa) and NPdelC(296-482 aa)] as well as the full-length NP(1-482 aa) were tested. Following mice immunisations, local lymph node cells were used as the source of lymphocytes and these cells were assessed to gauge the T cell responses. Stimulated splenocytes were analysed for lymphoproliferative responses and cytokine mRNA expression to evaluate T cell polarisation. Based on the data obtained, it appears that the amino-terminal region (1-135 amino acids) of NP is significantly more immunogenic than the other regions. In contrast, the carboxy-terminal region (296-482 aa) appears to play a suppressive role in cellular immune activation. Additionally, the middle region (136-295 aa) of the NP is identified as being responsible for inducing Th17-type cellular immune responses. In conclusion, this study points out to the specific regions of the CCHFV NP that are involved in shaping the cellular immune responses, representing a crucial step toward refining the structural elements contributing anti-viral immunity and providing a sound ground for modulation efforts.
Zika virus (ZIKV) is an emerging arbovirus belonging to the Flaviviridae family and Orthoflavivirus genus, with a pronounced tropism for the central nervous system (CNS), where it induces neuroinflammation and neuronal d...Zika virus (ZIKV) is an emerging arbovirus belonging to the Flaviviridae family and Orthoflavivirus genus, with a pronounced tropism for the central nervous system (CNS), where it induces neuroinflammation and neuronal death. ZIKV is known to exploit host cellular mechanisms, including the activation of survival pathways such as the PI3K/AKT signalling cascade, to evade apoptosis and enhance its replication. However, the role of the PI3Kγ isoform in ZIKV-induced neuroinflammation has not been previously explored, and this study aimed to investigate PI3Kγ in ZIKV pathogenesis. Primary neuronal cultures from PI3Kγ-deficient mice (PI3Kγ) and human neuroblastoma SH-SY5Y cells treated with the PI3Kγ inhibitor AS605240 were infected with ZIKV to assess the impact of PI3Kγ signalling on viral replication and neuronal survival. Additionally, interferon α/β receptor knockout (A129) mice were treated with AS605240 either before or after ZIKV infection to evaluate the pathway's role in neuroinflammation. In vitro, both genetic ablation and pharmacological inhibition of PI3Kγ suppressed ZIKV replication (~3% and ~17%, respectively) and prevented neuronal death (~16%). In vivo, mice treated with the PI3Kγ inhibitor exhibited enhanced protection against ZIKV infection, characterised by reduced viral load (~12%) and diminished brain and optic nerve damage. This neuroprotective effect correlated with reduced TNF production (about ~67%) by microglia. Furthermore, inhibition of PI3Kγ curtailed the recruitment and activation of CD8+ T cells and decreased the production of pro-inflammatory mediators, including IFN-γ and IL-17, in the brains of ZIKV-infected mice. These findings suggest that PI3Kγ activation facilitates ZIKV infection and exacerbates neuroinflammation. Pharmacological inhibition of the PI3Kγ pathway may offer therapeutic benefits by limiting viral replication and alleviating neuroinflammatory responses during ZIKV infection.
The intracellular, tick-borne bacterium Neoehrlichia (N.) mikurensis can cause neoehrlichiosis in patients with compromised B-cell defences, while immunocompetent individuals are frequently healthy carriers of the infect...The intracellular, tick-borne bacterium Neoehrlichia (N.) mikurensis can cause neoehrlichiosis in patients with compromised B-cell defences, while immunocompetent individuals are frequently healthy carriers of the infection. We hypothesised that N. mikurensis induces latent infections that reactivate when B-cell immunity is compromised. We tested this hypothesis by determining the incidence of N. mikurensis reactivation in 97 patients with B-cell lymphomas who were treated with anti-CD20 antibody therapy (rituximab) and evaluating the presence of N. mikurensis-specific T cells in latently infected individuals. Four patients (4%) reactivated N. mikurensis infection and four patients (4%) had asymptomatic infection before the initiation of B-cell suppression. All eight patients who were infected with N. mikurensis had N. mikurensis-specific, perforin-expressing Th1 and CD8+ T-cell populations with up-regulation of CXCL10 and IFN-γ, in contrast to the noninfected lymphoma patients who lacked these T-cell subsets. The infected lymphoma patients also had expanded γδ T-cell populations. This study supports the notion of latent, reactivatable N. mikurensis infections.
He XL, Zhou YT, Liu YM
… +6 more, Wu JY, Liu XN, Yi Q, Feng XX, Yu J, Li L
BMC Immunol
· 2026 Feb · PMID 41645055
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The role of Plasmacytoid Dendritic Cells (pDCs) in Enterovirus-71 (EV71)-induced Hand, Foot, and Mouth Disease (HFMD) remains unclear. In this study, we investigated pDCs in severe HFMD patients infected with EV71. Flow...The role of Plasmacytoid Dendritic Cells (pDCs) in Enterovirus-71 (EV71)-induced Hand, Foot, and Mouth Disease (HFMD) remains unclear. In this study, we investigated pDCs in severe HFMD patients infected with EV71. Flow cytometry revealed reduced pDC percentage in severe patients compared to healthy controls. In vitro, as EV71 replicated in pDCs, live cell numbers and levels of Interferon-alpha (IFN-a) and Interleukin (IL)-6 decreased, while IL-10 and Tumour Necrosis Factor-alpha (TNF-a) increased, particularly in critically ill patients. Notably, pDCs derived from critically ill patients exhibited significantly lower amplification rate and antiviral cytokine secretion compared to healthy controls. Analysis of the infection time course demonstrated that TLR7 expression rapidly increased at 6 h post-infection (h.p.i.), while its downstream signaling molecules reached higher levels by 24 h. TLR7 expression itself significantly decreased at 24 h.p.i. Pretreatment with the TLR7 inhibitor chloroquine (CQ) effectively suppressed the upregulation of TLR7. Concurrently, EV71 VP1 protein expression in the CQ-treated group remained at a moderate level throughout the time course, whereas it increased progressively in the untreated group. These findings suggest that EV71 may dynamically modulate the TLR7 pathway to evade innate immune recognition. In conclusion, EV71 may manipulate pDCs proliferation and cytokine secretion, evading the antiviral immune response, inducing cell tolerance, and promoting apoptosis. We speculate that EV71-induced inactivation of pDCs may contribute to disease deterioration.
Non-small cell lung cancer (NSCLC) is an aggressive malignancy necessitating innovative therapeutic approaches to augment antitumour immunity. Our study examined the function of the STAT2 protein in CD4 T helper cells, w...Non-small cell lung cancer (NSCLC) is an aggressive malignancy necessitating innovative therapeutic approaches to augment antitumour immunity. Our study examined the function of the STAT2 protein in CD4 T helper cells, which are essential for the immune response to cancer. We utilised CRISPR/Cas9 to ablate STAT2 in CD4 T cells from stage I NSCLC patients (n = 30), assessing its impact on cellular function and diverse epigenetic pathways. Our findings indicate that the depletion of STAT2 markedly enhances the anti-cancer efficacy of T lymphocytes. Deletion of STAT2 diminished oxidative stress, enhanced the synthesis of advantageous TH1 cytokines. STAT2 depletion reduced DNA methylation and R-loop formation. T cells deficient in STAT2 showed enhanced efficacy in activating cytotoxic T lymphocytes to eliminate cancer cells. These findings identify STAT2 as a crucial regulator of immune function in the lung cancer microenvironment. Targeted STAT2 inhibition in tumour-reactive T cells may reinstate anti-tumour immunity, although systemic inhibition requires further research on targeted intervention strategies.