Frontiers in Immunology最新文献

Objective: To evaluate the efficacy and coronary outcomes of tocilizumab (TCZ) in patients with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD), and to place these findings against the conflicting available evidence.

Methods: We retrospectively analyzed four patients with IVIG-resistant KD who received TCZ as rescue therapy. Clinical, laboratory, and echocardiographic data (coronary artery Z-scores) were collected before and after treatment.

Results: All patients received a second dose of IVIG before TCZ administration, however, symptoms did not improve. Following TCZ administration (median 15.5 days from onset), all patients achieved normothermia within 24 hours, accompanied by rapid normalization of inflammatory markers. Notably, no new coronary artery lesions (CALs) were identified after treatment. Additionally, in the two patients with pre-existing CALs, complete resolution of coronary dilation was observed during follow-up. No drug-related adverse events occurred.

Conclusion: In this series, late administration of TCZ during the subacute phase was associated with a rapid anti-inflammatory response and favorable coronary remodeling, including aneurysm regression. This outcome contrasts with previous reports of coronary dilation following earlier intervention. Critically, these observations lead us to propose a "phase-dependent efficacy" hypothesis: the timing of IL-6 blockade relative to disease stage may be a critical determinant of coronary outcomes. This hypothesis underscores the need to consider the disease phase when evaluating IL-6 blockade for refractory KD.

T cell-based immunotherapies have achieved notable success in the treatment of hematological malignancies, particularly through the application of chimeric antigen receptor (CAR) T cells. However, the clinical efficacy of such approaches in solid tumors remains limited due to a range of intrinsic and extrinsic barriers, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and insufficient T cell infiltration and persistence. Despite these challenges, significant advances have been made in recent years in the development of CAR-T cells, T cell receptor-engineered T cells (TCR-T), and tumor-infiltrating lymphocytes (TILs) for solid tumors. This review provides a comprehensive overview of the current landscape of T cell immunotherapies targeting solid tumors. We examine the underlying mechanisms and design principles of each therapeutic modality and summarize the clinical progress in a tumor-specific context. Particular attention is given to the biological and technical challenges that impede treatment efficacy, including antigen escape, on-target off-tumor toxicity, and the suppressive features of the TME. Furthermore, we discuss emerging strategies aimed at overcoming these obstacles, such as combinatorial antigen targeting, immune checkpoint blockade, synthetic biology tools, and gene editing technologies. Finally, we outline future perspectives in the field, emphasizing the importance of precision immunotherapy and the integration of multi-omics data to enhance T cell functionality and specificity. This review aims to inform ongoing research and guide the clinical translation of T cell-based therapies for solid tumors.

PDAC remains one of the most lethal malignancies, characterized by a highly desmoplastic ECM that promotes an immunosuppressive signaling network and dampens the effectiveness of traditional therapies. Among the several key contributors to its immune evasion pathways are chemokine signaling axes, which orchestrate the recruitment of regulatory immune cell populations, promote metastasis, and remodel the TME in favor of tumor progression. This review comprehensively examines the roles of major CCR-CCL signaling pathways-primarily focusing on the CCR2-CCL2, CCR5-CCL5, CCR4-CCL17/22, CCR6-CCL20, and CCR7-CCL19/21 axes-in PDAC development, detailing their expression patterns, immunologic impact, and downstream signaling mechanisms and outcomes. We further detail past and ongoing therapeutic efforts and trials addressing these axes in both PDAC and relevant non-PDAC settings via several small-molecule antagonists and monoclonal antibodies: BMS-813160, Maraviroc, Leronlimab, FLX475, PF-07054894, IDOR- 1117-2520, and CAP-100. Despite continuous advances in the field, the current body of evidence remains limited and presents significant research gaps in areas such as spatial profiling, stage-specific analyses, and general mechanistic validation in PDAC-specific settings. Addressing these shortcomings will be key to developing a more comprehensive knowledge of the field and improving future therapeutic strategies to overcome PDAC.

Introduction: The unfolded protein response (UPR) promotes prostate cancer (PCa) progression, yet its multi-omics landscape and clinical utility remain undefined.

Methods: We integrated single-cell and bulk transcriptomic datasets, and identified UPR-related genes (UPRRGs) through a combination of differential expression analysis and weighted gene co-expression network analysis (WGCNA), based on which we further developed a consensus UPR-related signature (UPRRS) using a machine learning framework. The UPRRGs were further characterized by functional enrichment, cell-cell communication, and survival analyses. A clinically applicable nomogram integrating UPR-related prognostic genes was constructed for prognostic prediction. Through in silico and in vitro analyses, we validated the clinical relevance between the hub UPRRGs and PCa progression.

Results: Single-cell analyses revealed elevated UPR activity in prostate epithelial cells, most prominently within the LE-KLK3 subpopulation. These cells exhibited enhanced ligand-receptor interactions in TNF, VEGF and NOTCH signaling axes. A seven-UPRRG signature (including IFRD1, DDIT3, HSPA5) demonstrated robust prognostic performance in the TCGA training set and three external validation cohorts (C-index > 0.82; AUC > 0.80). Multivariate Cox analysis confirmed UPRRS as an independent prognostic factor beyond clinical stage and Gleason score. Mechanistically, the UPRRS-high subgroup displayed an immunosuppressive microenvironment and reduced sensitivity to multiple chemotherapeutics. In vitro knock-down of IFRD1 markedly attenuated PCa cell proliferation and migration.

Conclusion: We provide the first systematic single-cell atlas of UPR heterogeneity in PCa and develop a clinically translatable UPRRS prognostic model. IFRD1, a key driver, emerges as a dual diagnostic and therapeutic target, offering both theoretical and experimental foundations for precision stratification and individualized management of PCa.

Objective: To compare overall survival (OS) and progression-free survival (PFS) between surgical resection and non-surgical therapy in initially unresectable Cholangiocarcinoma (CCA) patients who achieved radiologic/MDT-confirmed resectability after PD-1/PD-L1 inhibitors plus TKIs.

Methods: We performed a retrospective analysis of 47 patients with initially unresectable CCA admitted between June 2020 and December 2024. Based on post-conversion treatment strategies, patients were divided into non-surgical resection (NR) and surgical resection groups (SR). We collected detailed baseline clinical data, treatment-related parameters, and long-term survival outcomes for all participants. Overall survival (OS) and progression-free survival (PFS) were compared between groups, with recurrence-free survival (RFS) analyzed in the SR. Cox regression was used to identify prognostic risk factors.

Results: This study enrolled a total of 47 patients, including 23 in the SR and 24 in the NR. No significant differences were observed in baseline data between the two groups before conversion therapy. In the SR, the median overall survival (OS) was not reached, with 1-, 2-, and 3-year OS rates of 95.7%, 68.5%, and 68.5%, respectively. These survival outcomes were significantly superior to those observed in the NR, where the median OS was 28.5 months, and the 1-, 2-, and 3-year OS rates were 91.7%, 51.4%, and 17.6%, respectively (P = 0.026). Additionally, the SR exhibited a significantly longer median progression-free survival (PFS) of 19 months, with corresponding 1-, 2-, and 3-year PFS rates of 87.0%, 40.2%, and 25.2%. In contrast, the NR had a median PFS of 13.5 months and 1-, 2-, and 3-year PFS rates of 61.6%, 12.4%, and 12.4%, respectively (P = 0.025). Among patients in the SR, 21 cases (91.3%) achieved R0 resection, with no surgery-related mortality reported. The 1-, 2-, and 3-year recurrence-free survival (RFS) rates in this subgroup were 54.7%, 39.0%, and 29.3%, respectively.

Conclusion: For patients with initially unresectable CCA, PD-1/PD-L1 inhibitors plus TKIs can successfully downstage the tumor. Conversion surgery is safe and feasible, and surgical treatment can improve patients' OS and PFS.

Background: Kidney transplantation remains the treatment of choice for end-stage kidney disease. Maintaining immunosuppression within the appropriate therapeutic range is essential to prevent rejection and ensure long-term graft survival. This study evaluated the clinical relevance of different tacrolimus exposure metrics and their association with post-transplant outcomes in a real-world kidney transplant cohort.

Methods: Of 881 adult deceased-donor kidney transplants performed between 2011 and 2020 at Heidelberg University Hospital, 372 recipients with a functioning graft at day 180 met the inclusion criteria and were included in the final analysis. Tacrolimus trough levels between days 90 and 180 were used to calculate different exposure metrics, including intrapatient variability (IPV), maximum quotient, minimum trough levels, and the area under the curve (AUC) to approximate time spent below the therapeutic threshold. Outcomes analyzed included 5-year death-censored graft survival, 5-year overall graft and patient survival, 3-year rejection-free survival, and 3-year donor-specific antibody (DSA)-free survival.

Results: High tacrolimus IPV (≥30%) was associated with a 2.4-fold increased risk of rejection (95% CI 1.3-4.6; P=0.009). A high quotient (≥3.0) was linked to a 2.3-fold higher risk of rejection (95% CI 1.2-4.5; P=0.014) and showed a trend toward worse graft survival (HR 1.9; 95% CI 1.0-3.6; P=0.050). Prolonged time below target levels (<6 ng/mL; AUC ≥0.2) was significantly associated with increased risks of graft failure (HR 3.4; 95% CI 1.9-6.0; P<0.001), death-censored graft failure (HR 4.0; 95% CI 2.1-7.6; P<0.001), and patient death (HR 4.1; 95% CI 1.6-10.3; P=0.003). Minimum trough levels <5 ng/mL were also strongly associated with adverse outcomes, including graft failure (HR 3.2; 95% CI 1.8-5.7; P<0.001), death-censored graft failure (HR 4.0; 95% CI 2.1-7.8; P<0.001), patient death (HR 3.4; 95% CI 1.3-9.0; P=0.012), and rejection (HR 2.5; 95% CI 1.3-4.6; P=0.005). No association was observed between any of the exposure metrics and the development of DSAs.

Conclusions: Multiple markers of tacrolimus underexposure were independently associated with poor post-transplant outcomes. These findings underscore the critical importance of maintaining tacrolimus levels within the target therapeutic range during the early post-transplant period to optimize long-term kidney transplant outcomes.

Nucleic acids, long regarded as linear polymers, are now recognized to also exist in circular forms with profound biological significance in both eukaryotic hosts and viruses. This review synthesizes emerging insights into the diverse roles of circular RNAs (circRNAs) and other circular nucleic acids in viral infection and immunity. We first discuss the biogenesis and functions of host-derived circRNAs, emphasizing their complex interplay with innate immunity. These molecules display a striking duality-capable of activating antiviral defenses through pattern recognition receptors such as RIG-I and PKR, yet also exploited by viruses as modulators of immune evasion. We then examine how viral evolution has repeatedly converged on circular architectures, from the minimalist circular RNA genomes of viroids and hepatitis D virus (HDV) to transiently or covalently circularized RNA and DNA viral genomes. A particular focus is placed on hepatitis B virus (HBV), whose covalently closed circular DNA (cccDNA) serves as the persistent nuclear template driving viral replication and chronic infection. We summarize current understanding of cccDNA transcriptional regulation, host factors influencing its activity, and clinical biomarkers such as serum HBV RNA and HBcrAg that reflect cccDNA dynamics. Finally, we highlight the biotechnological applications of circularity, including circRNA-based vaccines offering superior stability and durable antigen expression, and circular nucleic acid probes for viral diagnostics. Collectively, this review positions circular nucleic acids as central players at the host-virus interface, shaping immunity, persistence, and the next generation of antiviral strategies.

Background: Major depressive disorder (MDD) and cardiovascular diseases (CVD) are mutually amplifying global health burdens, yet the causal directions and immune-determined molecular substructures that link MDD to myocardial infarction (MI) and heart failure (HF) remain poorly resolved.

Methods: Bidirectional two-sample Mendelian randomization (MR) was applied to large-scale GWAS (1.35 million MDD; 361 K MI; 977 K HF) followed by replication in 11,004 NHANES 2005-2020 participants using restricted cubic splines and multivariable logistic regression. Multi-cohort transcriptomics (peripheral blood microarray n = 447; in-house RNA-seq n = 14; left-ventricular tissue from dilated cardiomyopathy (DCM) patients (n = 332) were integrated to identify MDD-driven expression signatures. LASSO regression, CIBERSORT, ssGSEA, consensus clustering and GSVA were employed to derive diagnostic gene panels and immune endotypes.

Results: MR analyses provided genetic evidence consistent with a directional effect of MDD on MI (IVW β = 0.01, P = 4.6 × 10⁻⁶) and HF (IVW β = 0.19, P = 1.3 × 10⁻⁶) without reverse causation. Depression (PHQ-9 ≥ 10) has a dose-dependent nonlinear association with MI and HF (P<0.0001), with adjusted odds ratios (OR) of 1.80 (95% CI: 1.07-3.05) and 2.41 (95% CI: 1.45-4.00), respectively. A total of 202 MDD-related genes were identified through integrated transcriptomic analysis. After cross validation with the MI/HF dataset, six robust biomarkers (TMEM43, C1orf174, L3MBTL4, OR52N4, SLC25A20, MISP3) were screened. Risk-score models discriminated MI (AUC = 0.90-1.00) and HF (AUC = 0.95) in peripheral blood, but HF discrimination in cardiac tissue was modest (AUC = 0.60). Consensus clustering on 184 MDD-correlated genes stratified each CVD into two reproducible subtypes: a "homeostatic/pro-fibrotic" cluster enriched for ribosomal and cell-cycle pathways and an "inflammatory-metabolic" cluster characterized by NF-κB, TNF-α, IL-6, complement and coagulation activation.

Conclusions: Genetic, epidemiological, and multi-omic evidence supports a directional association between MDD and increased risk of MI and HF. We deliver reproducible blood-based gene panels and immune endotypes that dissect biologically distinct MDD-CVD substructures, offering actionable targets for precision immunomodulatory therapy in cardio-depressive comorbidity.