Hepato-biliary-pancreatic cancers, notorious for their pronounced heterogeneity and poor prognosis, continue to be a dominant factor in cancer-related deaths globally. Although immunotherapy has dramatically reshaped the cancer treatment landscape, its efficacy in these malignancies remains suboptimal due to the intense immunosuppression in the tumor microenvironment (TME) stemming from metabolic dysregulation. This review provides an in-depth analysis of the fundamental mechanisms of immunometabolic suppression. It highlights the strategies employed by tumor cells to compete with immune cells for nutrients, the accumulation of inhibitory metabolitessuch as lactate and adenosine, and disrupt pivotal metabolic pathways in CD8+ T, NK, and myeloid cells, ultimately leading to functional depletion. The novelty of this work lies in its systematic classification of these metabolic vulnerabilities and the introduction of a tripartite approach to address them: nutrient redistribution, metabolite scavenging, and enhancement of immune cell intrinsic metabolism. This approach aims to complement the next generation of immunotherapies, converting immunologically "cold" tumors into "hot" ones. Additionally, the review emphasizes the potential of integrating multi-omics profiling, artificial intelligence, and biomarker-guided personalized therapy as avenues to overcome resistance and enhance clinical efficacy. By viewing the challenge of therapy resistance through a metabolic perspective, this study not only enriches our foundational understanding of tumor-immune interactions but also presents a practical framework for designing highly efficacious combination therapies, representing a crucial advancement in the management of these formidable cancers.

Liver cancer is a highly heterogeneous malignancy, still representing a leading cause of cancer-related mortality worldwide. Its pathogenesis is complex and therefore not yet fully understood; however, emerging evidence highlights the interplay of genetic predisposition, environmental factors, and immune dysregulation. Tumor-associated autoantibodies (TAAbs) have recently been considered promising biomarkers thanks to their immune responses to aberrant tumor-associated antigens. These autoantibodies influence tumor progression through antigen recognition, immune surveillance, and microenvironment modulation, although their precise roles require further investigation. This review examines the multifaceted potential of TAAbs in liver cancer, including the description of their generation and function, detection methods, and clinical utility in early diagnosis, treatment monitoring, and prognosis. The liver cancer treatment strategy based on TAAbs is also described. Despite progress in this area, challenges remain regarding standardization, understanding of the mechanism of action, and clinical translation. Future research should integrate multidisciplinary and AI technology to develop TAAbs-based precision medicine strategies. Uncovering TAAbs-related immune networks will enable the development of diagnostic and therapeutic approaches, ultimately improving patient outcomes.

Peptidylarginine deiminases (PAD) 2 and 4 are pivotal enzymes in the pathophysiology of RA, owing to their involvement in protein citrullination, which produces autoantigens recognised by anti-citrullinated protein antibodies (ACPAs). Genetic variations in PADI2 and PADI4, along with autoantibodies targeting these enzymes, have been identified as significant contributors to the susceptibility and heterogeneity of RA. This systematic review with narrative synthesis consolidates existing evidence on the correlations between PADI2/PADI4 polymorphisms and the risk of RA, alongside the prevalence and clinical implications of anti-PAD2 and anti-PAD4 autoantibodies, with particular emphasis on identifying research deficiencies in underrepresented communities. A thorough literature review of PubMed, Web of Science, Scopus, Embase, and Google Scholar was performed until March 2024 for studies examining PADI2/PADI4 genetics or anti-PAD antibodies in patients with RA. No geographical or linguistic restrictions were applied. Forty-two genetic studies and 18 autoantibody studies were included. PADI4 polymorphisms exhibit notable relationships with RA in Asian populations (pooled odds ratio 1.23, 95% confidence interval 1.16-1.31); however, the results are equivocal among Europeans. A protective PADI2 variation (rs1005753) was discovered in Southeast Asians (OR = 0.87 (95% CI =0.77-0.99)). Anti-PAD4 antibodies (18-35% prevalence) were correlated with severe erosive disease, whereas anti-PAD2 antibodies (~18.5% prevalence) were correlated with milder disease. No studies pertaining to genetics or autoantibody profiles in African populations were found. Substantial advancements have been made in understanding PAD2 and PAD4 in Asian and European populations. The lack of data from African populations constitutes a significant research gap that necessitates immediate focus to guarantee the equitable implementation of biomarkers and therapeutic strategies.

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) functions as a critical hub connecting immune homeostasis and disease pathology. By recognizing "self"-associated sialylated modifications, it plays a complex and central role in maintaining physiological balance and driving disease progression. This review systematically integrates empirical research to comprehensively elucidate the biological basis of Siglec-9 and its mechanisms in various pathological states, including cancer, infection, chronic inflammation, neurodegenerative diseases, and metabolic disorders. Critically, dysregulated Siglec-9 signaling constitutes a shared pathogenic hub across diseases. Within the tumor microenvironment, it mediates immunosuppression and immune escape. During infections, pathogens exploit this pathway through molecular mimicry to evade host defenses, and its expression and genetic variants are significantly associated with susceptibility and severity in chronic diseases. Based on these mechanisms, Siglec-9 has emerged as a highly promising diagnostic biomarker, molecular imaging target, and therapeutic candidate. Intervention strategies, such as blocking antibodies, small-molecule inhibitors, and cell therapies, show significant preclinical promise. This review ultimately establishes the importance of targeting Siglec-9 and the related sialic acid-Siglec axis to develop innovative treatment strategies for various refractory diseases and identifies key directions and challenges for future translational research.

Germinal centers (GCs) are specialized microanatomical structures within secondary lymphoid organs where B cells undergo somatic hypermutation, affinity-based selection, and differentiation into high-affinity antibody-secreting plasma cells and memory B cells. In systemic lupus erythematosus (SLE), the dysregulated GC response is a major contributor to the production of pathogenic autoantibodies that promote immune complex formation and multi-organ damage. Autoantibodies are also produced through non-GC extrafollicular (EF) responses. This review examines the cellular and molecular mechanisms underlying GC and EF dysfunction in SLE, with emphasis on aberrant B cell selection and T follicular helper (Tfh) cell expansion, and metabolic reprogramming of these cells. We discuss current therapeutic strategies targeting GC and EF components, including B cell depletion and cytokine blockade, and highlight emerging approaches such as metabolic inhibitors and T follicular regulatory (Tfr) cell-based immunotherapy. Understanding the complex interplay between immune cells within dysregulated GC and EF responses offers promising avenues for developing more targeted and effective treatments for SLE while preserving protective immune responses.

Autoimmune diseases (AIDs) are chronic inflammatory disorders in which loss of self-tolerance intersects with tissue stress and damage. Increasing evidence indicates that regulated cell death (RCD) can act as an upstream amplifier in selected autoimmune settings, while in other settings it may mainly report downstream collateral injury caused by cytotoxic lymphocytes, immune complexes, complement activation, or tissue hypoxia. Accordingly, this review distinguishes causal death execution from associative pathway signatures and highlights the types of longitudinal, cell-type-resolved, and perturbational evidence needed to make that distinction. We summarize how apoptosis, necroptosis, pyroptosis, and ferroptosis operate as an interlocking network in autoimmune microenvironments, frequently co-existing as context-dependent mixed-death states driven by shared triggers such as cytokines, PRR ligands, and oxidative stress, and governed by decision hubs including RIPK1 and caspase-8. We highlight integrated concepts such as PANoptosis to explain pathway convergence and compensatory switching into parallel lytic branches when a single node is constrained. The review further connects mechanistic insights to translational priorities, emphasizing biomarker strategies that report pathway engagement, targeted modulation of executors or upstream sensing and cytokine circuits, and lesion-localized delivery approaches to improve the therapeutic window. Finally, we outline key gaps that must be addressed to enable precision interventions, including spatial and cell-type resolved validation of death programs, longitudinal profiling across flare-remission trajectories, and harmonized composite panels capable of capturing mixed-death dynamics in heterogeneous AIDs.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune dysregulation across the lifespan. Accumulating evidence suggests that many immunological alterations observed in SLE resemble those seen in physiological aging. Here, we review the major innate and adaptive mechanisms of immunosenescence in SLE, including telomere shortening, chronic low-grade inflammation, thymic dysfunction, and the expansion of senescent immune cell subsets. Of note, we discuss how these age-associated immune phenotypes emerge early and contribute to disease activity, organ damage, and long-term outcomes. Clinically, immunosenescence contributes to cardiovascular complications, frailty, increased infections, and cognitive impairment in SLE. Therapies targeting senescence-related pathways - including modulation of intracellular metabolic pathways and senolytics - are also discussed and constitute promise as emerging strategies.

Sjögren's syndrome (SS) is a systemic autoimmune disorder frequently associated with aqueous-deficient dry eye, driven by lacrimal gland dysfunction and chronic ocular surface inflammation. While immune dysregulation remains central to disease pathogenesis, emerging evidence may suggest that microbial communities at the ocular surface and along the gut-eye-lacrimal axis may contribute to ocular immune homeostasis and inflammatory disease expression. This review summarizes the composition and immunological functions of the healthy ocular surface microbiota and critically discusses available data on microbial alterations in SS-associated dry eye. Current human studies describe changes in ocular surface microbial diversity and composition, including shifts in commensal and potentially inflammation-associated taxa; however, these findings remain largely associative and are influenced by the low-biomass nature of ocular samples and methodological variability. Experimental evidence supporting a causal role for microbiota in ocular immune regulation derives mainly from murine models of gut microbiota manipulation or transfer, rather than from direct demonstration of causality for the ocular microbiome in human SS. These models may sugges that gut microbial communities may influence ocular surface barrier integrity, cytokine responses, and T-cell polarization, including the Th17/Treg balance. We also discuss microbial-derived metabolites, including short-chain fatty acids and indole derivatives, and their potential relevance to mucosal immune regulation. Overall, the ocular and gut-associated microbiome may represent an important interface between mucosal immunity and autoimmune dry eye in SS, but further studies are required before a causal role for the ocular microbiome itself can be established.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of rare, potentially life-threatening autoimmune disorders characterized by necrotizing inflammation of small vessels. Over recent decades, remarkable advances have been made in unraveling its immunopathogenesis, emphasizing the interplay between genetic predisposition, environmental triggers, loss of immune tolerance, neutrophil extracellular trap formation, and complement-mediated neutrophil activation. This review provides an integrative synthesis of recent mechanistic and clinical insights into AAV, bridging fundamental immunology with translational and therapeutic advances. Based on an extensive literature search of PubMed and Scopus, studies were selected according to methodological quality and clinical relevance. Distinct ANCA specificities, proteinase 3 (PR3) and myeloperoxidase (MPO), define overlapping yet prognostically divergent subsets, with PR3-ANCA linked to relapsing multisystem disease and MPO-ANCA to renal involvement and progression to kidney failure. Therapeutic paradigms have evolved from cyclophosphamide-based induction toward rituximab-centered and glucocorticoid-sparing regimens, with avacopan and mepolizumab further improving efficacy and safety profiles. Despite five-year survival rates exceeding 85%, long-term morbidity persists, driven by relapse and treatment-related toxicity. However, precision therapy in AAV remains incomplete, as current treatment selection is still guided mainly by disease severity, organ involvement, relapse risk, comorbidities, renal histology, and glucocorticoid-toxicity risk rather than by validated molecular biomarkers. Emerging data on complement activation, urinary inflammatory biomarkers, B-cell kinetics, and tissue-based transcriptomic profiling may refine disease endotyping and individualized monitoring. Collectively, these advances herald a transition from empirical immunosuppression toward biologically informed, precision-oriented care in vasculitis.

HLA-B27 exemplifies an evolutionary trade-off between protection against infection and susceptibility to inflammatory disease. To investigate its long-term population history, this study examined three HLA-B27-tagging variants-rs116488202, rs4349859, and rs116666910-in present-day populations from UK biobank and 1000 Genomes Project, and in 15,836 ancient West Eurasian individuals. The estimated frequency of HLA-B27 reached 49.0% approximately 8500 years before present, then declined progressively to 3.9% in the present-day reference population. Comparison with genome-wide association study (GWAS) data for ankylosing spondylitis (AS) showed that HLA-B27-linked alleles conferring increased disease risk had negative selection coefficients, indicating sustained selection against HLA-B27 over the past 10,000 years. The decline coincided with major Holocene changes in settlement and subsistence patterns, microbial exposure, and enteric infection, which may have increased the inflammatory costs of HLA-B27. Because previous paleopathological studies have largely been limited to identifying advanced skeletal manifestations of AS, this ancient genetic study may provide currently the most sensitive population-level record of an otherwise largely undetectable, epidemic-scale disease burden in antiquity. These findings support the hypothesis that HLA-B27-associated spondyloarthritis was sufficiently prevalent and severe to influence human evolution in prehistoric West Eurasia.

Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.

This study concentrates on problems related to the inadequate integration of the causality principle, and on central historical data that are disregarded in SLE research. Three research areas will be critically discussed: i. Role of SLE-associated causality principle and causality cascade; ii. Definition and clinical impact of anti-B DNA structure-specific and anti-chromatin-specific antibodies; iii. Incompatible pathogenic models that account for lupus nephritis, and their individual theoretical impacts on causal therapy development. A main motivation is to revitalize ignored but highly important historical milestone discoveries, and documentation of concrete problems that have not been studied seriously like nosology connected to rationalizing SLE as a disease entity. This study covers description of anti-DNA antibody structures and anti-chromatin antibodies; their origins, and their impact on operational molecular and cellular processes accounting for lupus nephritis. The reflections around autoimmune diagnostics and pathophysiology provide information connected to "SLE as an enigmatic prototype autoimmune syndrome". We need to implement causality as a central element to promote rational hypotheses that may make SLE logic and intellectually understandable. This is critical if the research aim is to develop causal therapies. The manuscript is analytical in nature and provides solutions to central problems that may resolve the causality cascade, a systemic element of causation that define SLE as a rational and delimitated syndrome. We have to bring to the discussion forum processes connecting DNA/chromatin structures with tolerance and immunity, inflammation, pathogenesis of lupus nephritis - and to replace classification criteria with causality-related diagnostic criteria.