Diabetic foot ulcer (DFU) is a chronic inflammatory disease because of persistent hyperglycemia. The pathophysiology of DFUs is mediated by chronic inflammation, decreased angiogenesis, and altered extracellular matrix (ECM) remodeling. Impaired immune response halts the DFUs in the inflammatory phase of healing without progressing them to the resolution phase, resulting in delayed healing. This suggests that immunomodulation of the DFU microenvironment may be beneficial in promoting wound healing by subsiding chronic inflammation, promoting angiogenesis, and ECM remodeling. This narrative review focuses on summarizing the upcoming strategies and research in immunomodulation to promote healing in DFUs in recent years. The review has discussed the role of small molecules, exosomes, hydrogels, and natural compounds tested in preclinical trials to promote wound healing, followed by the limitations and future directions.

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Sex- and gender-related differences profoundly influence immune responses to SARS-CoV-2 infection and vaccination but remain insufficiently considered in research and public health strategies. This review explores how sex, gender, age, and the exposome interact to shape susceptibility to coronavirus-19 disease (COVID-19), disease severity, Long COVID, and vaccine-induced immunity. Males experience higher rates of severe disease, hospitalisation, and mortality, whereas females generally mount stronger innate and adaptive immune responses, contributing to greater resilience. These differences arise from a complex interplay between biological factors and gender-related determinants, including occupational exposures, healthcare access, health-related behaviours, socioeconomic conditions, and the microbiota, which contribute to the individual exposome. This review also highlights the impact of ageing on SARS-CoV-2 immunity, highlighting the preserved immune regulation observed in centenarians, which may contribute to protection against severe COVID-19 despite advanced age. Current evidence on Long COVID is discussed, including its higher prevalence among females and the sex-specific immunological pathways that may underlie persistent symptoms. We examine age-, sex-, and gender-related differences in vaccine response, distinguishing efficacy from effectiveness. Although females generally mount stronger antibody responses, this advantage does not necessarily translate into greater clinical protection. The relative benefit of vaccination appears greater in males because of their higher baseline risk of severe disease. Finally, we discuss how exposomic factors, including lifestyle, microbiota composition, and environmental and social determinants, influence vaccine responsiveness and hesitancy. Integrating sex, gender, age, and the exposome perspectives is essential for developing more equitable and personalised strategies to prevent and manage COVID-19 and future emerging diseases.

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Vitamin B12 (cobalamin) is an essential water-soluble micronutrient serving as a cofactor for key enzymes in one-carbon metabolism and mitochondrial energy production. Beyond its classical roles in hematopoiesis and neurological function, emerging evidence demonstrates that vitamin B12 has emerging immunometabolic roles. Through its role in methionine synthase-dependent one-carbon metabolism, cobalamin contributes to DNA synthesis, methylation reactions, and redox homeostasis—processes critical for the proliferation, differentiation, and function of both innate and adaptive immune cells. Deficiency has been associated with impaired immune responses and may contribute to altered susceptibility to infections and inflammatory disorders. Conversely, adequate cobalamin status restores methylation potential, mitochondrial bioenergetics, and redox homeostasis, potentially supporting T and B cell function and regulatory immune pathways, and modulating pro- and anti-inflammatory cytokine networks. Most evidence derives from deficient or high-risk populations, whereas immunomodulatory effects in vitamin B12-replete individuals remain uncertain. This review provides a comprehensive synthesis of mechanistic and clinical evidence, emphasizing vitamin B12 as a critical immunometabolic regulator and exploring its potential therapeutic applications in immune-mediated and inflammatory disorders.

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Obesity is a major global health challenge, now recognized as a complex metabolic and inflammatory disorder characterized by excess adiposity and chronic low-grade inflammation. Adipose tissue functions as an endocrine organ, secreting adipokines that regulate metabolism and immune responses. Among these, Isthmin-1 (ISM1) has recently emerged as a novel adipokine with important metabolic and anti-inflammatory roles. ISM1 is widely expressed in adult tissues and is associated with central adiposity and metabolic dysfunction. It enhances glucose uptake via an insulin-independent PI3K/Akt pathway through integrin αVβ5 activation, promoting GLUT4 translocation. ISM1 also regulates lipid metabolism by inhibiting lipogenesis and stimulating fatty acid oxidation. Additionally, it exerts anti-inflammatory effects by suppressing NF-κB signaling and promoting macrophage polarization toward an anti-inflammatory phenotype. Exercise is known to improve adipokine profiles, insulin sensitivity, and inflammation, but its effects on ISM1 remain unexplored. This represents a critical gap in the literature. Understanding how different exercise modalities influence ISM1 could reveal new mechanisms underlying exercise benefits and support its potential as a biomarker or therapeutic target in obesity and metabolic disorders.

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Human γδ T cells represent a minor subset of lymphocytes present in the peripheral blood. This lymphocyte subset is mainly localized within the mucosae of airways and gut. In the latter context, γδ T cells can represent a key immune cell subset involved both in regulating intestinal homeostasis and in responding to pathogens and colorectal carcinoma (CRC) growth. γδ T cell subsets such as the Vδ2⁺ respond to phosphate antigens produced by bacteria, while Vδ1⁺ cells can exert an immune response after mucosal stress stimuli. γδ T cells do not recognize as classical αβ⁺ T cells the peptide antigens in the context of major histocompatibility complex (MHC). γδ T cells may play a complementary role with αβ⁺ T cells in mucosal immunity at the gastrointestinal barrier. Colon γδ T cells can exhibit antitumor properties and regulatory functions. Indeed, human γδ T cell subsets present in the gut bear some activatory receptors, such as NKG2D and DNAX Accessory Molecule (DNAM)-1, leading to the elimination of CRC cells. By contrast, γδ T cells producing interleukin (IL)-17, transforming growth factor β, and amphiregulin show pro-tumor activity. This dual property of γδ T cells poses challenges for their use as an immunotherapeutic tool, while the MHC-independent recognition of antigens can support their use as off-the-shelf allogeneic cells.

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Neuroimmune disorders are increasingly understood not as the consequence of dysfunction in isolated cell types, but as dynamic diseases shaped by coordinated transitions across interacting neural and immune cell states. This narrative review synthesizes current evidence showing how microglia, astrocytes, neural stem cells, vascular elements, and infiltrating peripheral immune cells shift between homeostatic, inflammatory, reparative, and disease-associated states in response to injury, infection, degeneration, and metabolic stress. We highlight how cytokine signaling, damage-associated molecular patterns, oxidative and metabolic stress, and transcriptional and epigenetic reprogramming reshape neuroimmune behavior across these cellular populations, thereby influencing inflammation, synaptic remodeling, tissue repair, and disease progression. By framing neurological disorders as state transition networks rather than static cellular abnormalities, this review integrates emerging insights from single-cell and spatial profiling with systems-level neuroimmunology and identifies cellular plasticity as both a mechanistic principle and a therapeutic opportunity. This perspective provides a unifying conceptual framework for understanding neuroimmune pathology in disorders such as Alzheimer’s disease, multiple sclerosis, stroke, and traumatic brain injury, while also pointing toward next-generation strategies that selectively modulate maladaptive cellular programs and promote regenerative neuroimmune states.

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The efficacy of viral vector-based vaccines is essential to provide long-term protection and prevention of emerging epidemics and pandemics in parallel to other vaccine platforms. The key challenges of achieving high vaccine efficacy relate to the engineering of highly potent antigens and the generation of long-lasting immunogenicity. Appropriate vaccine development also includes the ability to quickly react to emerging variants and their effects on vaccine efficacy. It can be achieved by booster vaccinations, rapid re-engineering of existing vaccines, but also by targeting conserved regions less prone to mutations, limiting the decrease in efficacy against new variants. Additional aspects involve alternative administration routes, for example, for respiratory infections, the application of intranasal delivery, which can enhance antigenicity and prolong vaccine action. Application of self-amplifying RNA can further potentially improve vaccine efficacy. Vaccine hesitancy has raised concerns about successful coverage of vaccine campaigns. The anti-vaccine campaigns based on misinformation and disinformation have caused serious damage to vaccinations during the Coronavirus disease 2019 (COVID-19) pandemic and to the spread of other infectious diseases.

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Tuberculosis (TB) accounts for the most deaths amongst humans from an infectious agent. Although the approved vaccines are effective in preventing infant meningitis, they provide inadequate protection for adolescents and adults. There is a need for an improved understanding of immunological determinants of protection from disease as well as the drivers of pathology. Tertiary lymphoid structures (TLS), inducible bronchial-associated lymphoid tissue (iBALT), are an organized accumulation of cells that mount a protective immune response against Mycobacterium tuberculosis (Mtb) in the lung. A comprehensive search of literature was performed in public databases for articles discussing iBALT in TB disease, yielding findings mainly from animal models of pulmonary TB and observational human data. The search revealed a protective role of iBALT characterized by efficient T-cell priming and macrophage activation that restricts Mtb spread. Conversely, dysregulated or chronic TLS formation is associated with excessive cytokine production, myofibroblast activation, autoimmunity, and the progression of post-TB lung disease (PTBLD). Future research must leverage omics technologies to delineate the stromal and immune subsets that govern the protective or pathological iBALT mechanisms.

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Autoimmune rheumatic diseases arise when the immune system transitions from a flexible, self-regulating network into a metabolically and epigenetically fixed inflammatory attractor state. This review synthesizes emerging evidence that immune tolerance is governed by a coupled epigenetic-metabolic axis integrating mitochondrial fitness, chromatin accessibility, redox balance, and nutrient flux across lymphoid, myeloid, and stromal compartments. We examine how chronic cytokine signaling, hypoxia, and oxidative stress destabilize regulatory programs, imprint glycolytic effector states, and remodel enhancer landscapes, thereby sustaining autoreactive circuits even after inflammatory pathways are pharmacologically suppressed. Multi-omic and spatial analyses reveal that pathogenic chromatin architectures, persistent mitochondrial dysfunction, and intercellular metabolite exchange cooperate to establish self-sustaining inflammatory ecosystems in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren’s syndrome. We further highlight therapeutic strategies aimed at tolerance reprogramming, including metabolic correction, chromatin-targeted agents, chimeric antigen receptor regulatory T cells (CAR-Tregs), tolerogenic dendritic cells, and integrative biomarkers that quantify metabolic-epigenetic coherence. By reframing autoimmunity as a disorder of energetic and chromatin desynchronization rather than isolated immune activation, this review outlines a mechanistic path toward durable, drug-free remission through deliberate restoration of the molecular architecture that maintains immune self-recognition.

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The intricate involvement of glial cells in chronic pain mechanisms represents a paradigm shift in our understanding of pain processing. From microglial-mediated neuroinflammation to astrocytic modulation of synaptic function, glial cells emerge as critical players in the complex neurobiology of chronic pain. As research continues to unravel the multifaceted roles of these cells, novel therapeutic targets and strategies are likely to emerge, potentially revolutionizing the management of chronic pain conditions. Chronic pain is complicated by frequent comorbidities such as fatigue, sleep disturbances, cognitive impairment, and mood disorders. Here, we hypothesize that neuroinflammatory processes are at the root of pain chronification and serve as the common thread linking characteristic hypersensitivity with the cognitive and emotional comorbidities typically associated with chronic pain.

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Obesity is a major global health challenge characterized by chronic low-grade inflammation and metabolic dysfunction. Among lipid-derived mediators involved in inflammation resolution, maresin-1 (MaR1)—a specialized pro-resolving mediator derived from docosahexaenoic acid (DHA) and produced mainly by M2 macrophages—has attracted increasing attention due to its potent anti-inflammatory and metabolic regulatory properties. MaR1 promotes the resolution of inflammation by limiting neutrophil infiltration, enhancing macrophage efferocytosis, and shifting cytokine profiles toward an anti-inflammatory phenotype. In addition, it modulates metabolic pathways related to insulin sensitivity and skeletal muscle glucose uptake through signaling mechanisms involving Akt and AMP-activated protein kinase (AMPK). Reduced circulating levels of MaR1 have been consistently associated with metabolic disorders, including obesity, type 2 diabetes, and cardiovascular disease, highlighting its potential as a biomarker of metabolic health. Exercise is a cornerstone non-pharmacological strategy for obesity management and activates molecular pathways—such as AMPK and Sirtuin 1 (SIRT1)—that overlap with those regulated by MaR1. However, human studies examining how different exercise modalities influence MaR1 production remain scarce. This perspective highlights the mechanistic links between exercise and MaR1 biology and proposes a translational research agenda to investigate how aerobic, resistance, and high-intensity interval training modulate MaR1 levels. Understanding this exercise–MaR1 axis may help establish MaR1 as a biomarker of exercise responsiveness and support the development of targeted lifestyle interventions for metabolic disease management.

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Opioids remain central to managing moderate to severe pain, yet they also produce significant and often under-recognized effects on the immune system. In this narrative review, we synthesize evidence from 1994 to 2025 across preclinical, translational, observational, and limited interventional studies in adults to examine how different opioid classes modulate immunity and the clinical relevance of these effects. Opioids act directly on immune cells via mu-opioid receptors (MORs), nociceptin/orphanin FQ receptors (NOR), and Toll-like receptor 4 (TLR4), and indirectly through neuroendocrine, autonomic, neuroinflammatory, and gut microbiota-mediated pathways. Immunologic consequences are drug specific: Morphine, fentanyl, and to a lesser extent methadone exhibit pronounced immunosuppressive profiles; oxycodone appears comparatively less suppressive; and buprenorphine and tramadol generally preserve, and may in some contexts enhance, immune function. Clinically, chronic or intensive opioid exposure is associated with increased risk of infection and sepsis-related mortality, potential facilitation of tumor progression or recurrence, impaired perioperative and transplant outcomes, and contributions to tolerance and opioid-induced hyperalgesia, with convergent data indicating these immune effects are intrinsic to opioid pharmacology. Framing opioid-induced immunomodulation as a clinically meaningful, agent-specific phenomenon argues for incorporating immunologic risk into analgesic selection—prioritizing less immunosuppressive opioids where appropriate, considering rotation and tapering strategies, using peripherally acting antagonists, and implementing multimodal analgesia—while underscoring the need for standardized immunologic endpoints, rigorously controlled clinical studies, and development of next-generation analgesics that maintain effective pain relief while minimizing detrimental immune effects.

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