Signal Regulatory Protein Alpha (SIRPα) and CD163 are associated with prognosis in esophageal cancer, but their prognostic value in blood is unknown. We retrospectively analyzed a randomized controlled trial of patients undergoing surgery for esophageal cancer. Soluble SIRPα (sSIRPα) and CD163 (sCD163) were measured using enzyme-linked immunosorbent assays in serum collected on the day of surgery and postoperative day 30. Patients were followed for one year. 68 patients were included. In patients undergoing upfront surgery (n = 15), high sSIRPα predicted increased 1-year mortality and sSIRPα <23.35 μg/L identified a low-risk subgroup (N = 7/15, 46.7%) with 100% 1-year survival. In contrast, among patients receiving neoadjuvant chemotherapy (CROSS or FLOT, n = 53), low sSIRPα predicted increased 1-year mortality and sSIRPα >26.15 μg/L identified a low-risk subgroup (N = 31/53, 58.5%) with 100% 1-year survival. There was no prognostic value in sCD163. In conclusion, neoadjuvant treatment may influence the prognostic value of sSIRPα in esophageal cancer.

Invariant natural killer T cells are uniquely positioned at the interface of innate and adaptive immunity, combining CD1d-restricted antigen recognition with rapid, diverse cytokine responses and relatively low HLA-driven alloreactivity. These properties make them attractive candidates for adoptive cellular immunotherapy, yet clinical translation has remained limited by inconsistent potency and persistence. This review considers ex vivo expansion as a determinant of product state rather than a passive scale-up step. Cytokine support, antigen and co-stimulatory signals, restimulation schedule, and culture duration can alter iNKT cell subset composition, survival, phenotype, and effector function, thereby influencing therapeutic fitness. We further discuss how human iNKT cell developmental biology and subset heterogeneity provide a framework for interpreting donor variability and culture-induced drift. We also compare peripheral-blood, hematopoietic stem/progenitor cell (HSPC)-derived, and induced pluripotent stem cell (iPSC)-derived manufacturing platforms and propose critical quality attributes (CQAs) for identity, potency, persistence, survival, and manufacturing safety. Progress will require manufacturing strategies that achieve clinically relevant expansion while preserving a defined and functionally validated cell state.

Bi-functional recombinant hybrid anti-PD-L1-IgGA antibody combines the effector functions of IgG and IgA and is also directed against the ligand of the programmed cell death1 receptor (PD-L1) to enhance cancer immunotherapy. Blocking the PD-1/PD-L1 signaling pathway using anti-PD-L1-IgGA is an effective new therapeutic approach that restores the functions of immune cells to kill cancer with high efficacy. In this study, the developed novel functional and high affinity human recombinant cross-isotype IgGA antibodies to PD-L1 were successfully produced in mammalian expression systems. We demonstrated that anti-PD-L1-IgGA has high specific binding activity to PD-L1 protein. FPIA analysis yielded a Kd of approximately 1.14 nM PD-1/PD-L1 blockade for determining the inhibition activity of anti-PD-L1 antibody was shown by TR-FRET-based blockade assay. Cross-isotype anti-PD-L1-IgGA antibodies may provide a basis for further development in cancer immunotherapy.

Extrahepatic cholangiocarcinoma (ECCA) is an aggressive malignancy with poor prognosis and few treatment options, partly due to CD8[+]T cell exhaustion in the tumor microenvironment. The role of TIGIT in driving this process remains mechanistically unclear. Using patient-derived immunocompetent cultures (iPDCs), we show that TIGIT blockade in ECCA reverses exhaustion by downregulating TOX and restoring TCF-1. In mouse CD8[+] T cells, transcriptomic analysis identifies the PI3K/AKT-FOXO1 axis as a critical mediator. Mechanistically, TIGIT suppresses AKT phosphorylation, leading to FOXO1 nuclear translocation, where FOXO1 directly binds the TOX promoter and activates its transcription. Together, these findings establish the TIGIT-PI3K/AKT-FOXO1-TOX axis as a core pathway driving CD8[+]T cell exhaustion in ECCA, filling a key mechanistic gap and offering new therapeutic targets for immunotherapy.

The goal of these studies was to elucidate the relationship between levels of autoantibodies and complement (C3/C4) in the sera of patients with systemic lupus erythematosus (SLE) and thereby provide a framework for interpreting serological biomarkers in the context of current therapy. Anti-RNA-binding proteins (RBPs) were measured by enzyme-linked immunofluorescence assay (ELFA); ANA and autoantibodies to C1q and dsDNA were measured by ELISA; and levels of C3 and C4 were measured by immunoturbidimetry. In univariate analyses, anti-dsDNA, anti-C1q, anti-Sm, anti-U1RNP, and anti-RNP-70 were associated with low C3 and low C4 levels. In Lasso logistic regression and decision tree analysis, however, only anti-dsDNA and anti-C1q showed a relationship with complement in contrast to the other antinuclear antibodies. These studies support the important relationship between levels of anti-dsDNA and complement and further suggest that anti-C1q antibodies may also lead to complement activation, alone or in concert with other autoantibodies.

We recently characterized the microenvironment of Anaplastic Thyroid Carcinoma (ATC) as immune-exhausted, rich in TIM-3-expressing exhausted cytotoxic T lymphocytes (CTLs). PD-1 was notably the least frequently expressed immune checkpoint (ICP). The results provided a potential explanation for the limited efficacy of anti-PD-1/PD-L1 immunotherapy, highlighting TIM-3 as another promising target. This pilot study further evaluated the potential efficacy of targeting TIM-3 in ATC as a therapeutic strategy in an in vitro model. A co-culture model of ATC cell line 8505C with exhausted TIM-3+ve/PD-1+ve CTLs was established and treated with anti-TIM-3 and anti-PD-1 antibodies, alone and in combination. Antibody efficacy was evaluated using flow cytometry, measuring Granzyme B and Perforin for CTL cytotoxic activity, and Annexin V and propidium iodide for tumor cell death. Additionally, differential gene expression before and after ICP blockade was analyzed using the NanoString nCounter Immune-oncology panel. Both individual and combined antibody treatments enhanced CTL cytotoxicity and promoted tumor cell death. Interestingly, ICP inhibition induced an upregulation of immune-activating pathways and downregulation of genes associated with tumor progression. These findings support the potential of TIM-3 blockers as an alternative to or in combination with anti-PD-1 therapy, thereby providing a rationale for further clinical investigation.

Anti-amyloid-β monoclonal antibodies have established immunotherapy as a viable approach for Alzheimer's disease, yet all α-synuclein and tau antibodies tested to date have failed clinically. These setbacks offer invaluable immunology lessons reshaping next-generation therapeutic development. Four key lessons emerge: epitope specificity determines outcomes, with mid-domain and microtubule-binding region antibodies showing promise over failed N-terminal approaches; biomarker-driven stratification using p-tau217 and AI algorithms can unmask efficacy in rapid progressors; most patients harbor mixed proteinopathies, rendering monotherapy insufficient and mandating combination immunotherapy; and neuroinflammation, particularly NLRP3 activation and microglial dysfunction, represents a convergent pathway targetable independently of upstream triggers. Emerging approaches include conformation-specific antibodies, protein-protein interaction inhibitors, and immune checkpoint targeting, such as anti-SIGLEC-10, to restore phagocytosis. These insights inform biomarker-enriched trials and combination regimens, although clinical evidence for specific combinations remains limited and requires validation. The systems framework targeting aggregation, neuroinflammation, and immunity offers a promising paradigm yet awaits empirical testing.

Autoantibodies in the plasma demonstrate potential as biomarkers for early detection of breast cancer. Copper transport proteins ATP7A, ATP7B and COPT1, are represent potential diagnostic biomarkers. This study aims to evaluate the diagnostic value of plasma autoantibodies targeting ATP7A, ATP7B and COPT1 in breast cancer. The plasma expression levels of anti-ATP7A/ATP7B/COPT1 autoantibodies were detected in the cohort with 229 patients with breast cancer (BC), 214 patients with benign breast tumor (BBN), and 169 normal controls (NC) using the ELISA method. The expression levels of three autoantibodies were significantly lower in BC compared to BBN and NC groups. The combination of anti-ATP7A and anti-COPT1 could improve the diagnostic efficacy with an increased AUC value (AUC = 0.844, 95% CI, 0.764-0.925) in patients aged ≤50 years with early HER2+ breast cancer. This study demonstrates the clinical value of these three autoantibodies in the detection of BC, suggesting their potential as diagnostic biomarkers for BC.

Multiple sclerosis (MS) is treated with branded or generic disease-modifying therapies (DMTs), with increasing concern for the composition and quality of off-patent products. Our objective was to evaluate differences in disease-specific biomarkers, a potential indicator of suboptimal therapeutic exposure, between individuals treated with branded and generic DMTs. We compared biomarker variability in MS individuals (n=1,124) treated with generic or brand-name fumarates (diroximel fumarate, dimethyl fumarate (DMF)), fingolimod, and teriflunomide. In the generic DMF group, higher coefficients of variation (COV) for CXCL9, CCL20, and TNFSF13B were observed, with a paradoxically lower variability for CXCL13. Higher COVs for CXCL9 were observed with generic fingolimod and for CXCL9 and CXCL13 with generic teriflunomide when compared to brand. Additionally, all generic DMTs demonstrated higher multi-variable variability index values across 18 proteins associated with MS disease activity. Greater biomarker variability with generic formulations may reflect differences in therapeutic exposure and less consistent disease control.

Hepatocellular carcinoma (HCC) develops within a chronically inflamed and immunologically dysregulated hepatic microenvironment that contributes to therapeutic resistance and disease progression. Gasdermin-mediated pyroptosis has emerged as a context-dependent inflammatory cell-death program capable of reshaping antitumor immunity, stromal remodeling, and immune checkpoint responsiveness. Acute and localized activation of GSDMD or GSDME may enhance immune-cell recruitment and tumor antigen exposure, whereas persistent pyroptotic signaling promotes fibrosis, angiogenesis, and immunosuppressive remodeling. This review examines the molecular circuitry linking pyroptosis with inflammasomes, metabolic stress, mitochondrial dysfunction, hypoxia, and epigenetic regulation in HCC. We further discuss how single-cell and spatial transcriptomic approaches reveal distinct pyroptotic immune niches associated with macrophage polarization, T-cell infiltration, and therapeutic response. Emerging therapeutic strategies including inflammasome modulation, gasdermin-targeted interventions, metabolic sensitization, and combination immunotherapy are also evaluated. Collectively, regulated pyroptosis may represent a promising immunomodulatory framework for improving precision therapy in HCC.

Immune checkpoint dysregulation contributes to cytotoxic lymphocyte exhaustion in hematologic malignancies. TIGIT, an inhibitory immune receptor expressed on activated T and natural killer (NK) cells, is a key regulator of immune exhaustion. However, its transcriptional landscape in pediatric acute lymphoblastic leukemia (ALL) remains unclear. TIGIT expression was investigated using institutional clinical samples, TARGET-ALL bulk RNA sequencing, and single-cell RNA sequencing data (GSE154109). TIGIT expression was significantly elevated in pediatric B-ALL compared with healthy controls (p = 0.0141), with preliminary discriminatory capacity (AUC = 0.875) in this exploratory cohort. Exploratory subgroup analyses suggested higher TIGIT expression in some clinical subgroups. Subgroup findings were interpreted conservatively in view of the limited sample sizes. Bulk transcriptomic analysis of 1587 TARGET-ALL samples detected TIGIT in 10%, suggesting a distinct subset. Single-cell transcriptomics revealed TIGIT expression in CD8[+] T cells and NK cells. Pathway analysis showed suppression of antigen presentation and interferon signaling, while cytotoxic cells exhibited transcriptional features consistent with exhaustion. Together, these findings provide preliminary evidence linking TIGIT expression to immune exhaustion-related transcriptional signatures in pediatric B-ALL. This interpretation is based on transcriptomic evidence and remains provisional pending protein-level and functional validation.

The adaptive autoimmune process in SLE is complex, and conventional techniques cannot resolve disease-associated T/B lymphocyte clones at a single-cell granularity. Single-cell RNA sequencing combined with single-cell V(D)J sequencing (scRNA+VDJ-seq) enables simultaneous profiling of cellular transcriptomes and TCR/BCR repertoires. This review highlights recent advances in scRNA+VDJ-seq in SLE and related autoimmune disorders, elucidating the link between receptor clonality, gene expression, and effector phenotypes. It delineates clonal expansion, biased V(D)J usage, and aberrant exhaustion in SLE, and compares T/B cell immune phenotypes across lupus nephritis, RA, pSS, and AS. The review also summarizes CD19 CAR-T and PD-1 agonist applications. Furthermore, it discusses AI integration with scRNA+VDJ-seq to analyze autoreactive T/B cells in SLE: from data integration to clinical translation, and assesses the clinical translational potential of this technology, offering novel targets and strategies for SLE diagnosis, personalized treatment, and prognosis.