Immune

Despite being defined pathologically by amyloid-β plaques, chronic neuroinflammation and neurofibrillary tangles, the drugs that target these processes directly (lecanemab and donanemab) have only modest effects on the clinical course of Alzheimer's disease (AD) and significant safety concerns have been identified, so there is renewed interest in upstream, systemic contributors to disease. This review aims to provide a synthesis of the latest mechanistic and clinical evidence that gut microbiota dysbiosis is associated with Alzheimer's disease with a specifically immunopharmacological focus. We will explore how the gut-brain axis pathways (vagal, immune, endocrine and microbial-metabolite signaling) converge to trigger microglial and astrocytic activation via toll-like receptor 4/NF-κB and complement-primed NLRP3 inflammasome signaling, which is also directly activated by amyloid-β and tau. Then we review the immunopharmacological interventions intended to break this axis - probiotic supplementation (some consistent benefit - although mild) and sodium oligomannate, with strong preclinical and case report signals that need human trials (in 2026) and polyphenols and GLP-1 receptor agonists, which have a persistent disconnect between mechanistic promise and clinical efficacy, including a definitive null result for semaglutide in 2026. Translative directions are addressed to nanotechnology-based delivery systems for improving bioavailability and blood-brain barrier penetration, as well as emerging precision-medicine, AI-driven approaches in the selection of treatments based on microbiome information. It is our opinion that because the gut-brain-immune axis is a mechanistically supported and potentially highly scalable therapeutic target, complementary to amyloid and tau therapies, the development of future therapies should match the inflammatory, metabolic and microbial phenotypes.

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are produced in enteroendocrine L cells and control energy homeostasis. GLP-1 receptor (GLP-1R) activation improves glucose homeostasis and induces satiety and weight loss, whereas GLP-2 receptor (GLP-2R) signaling promotes intestinal growth and nutrient absorption. GLP-1R and GLP-2R agonism also reduce intestinal damage in preclinical studies. Here, we demonstrate that endogenous GLP-1R and GLP-2R signaling are essential for protecting the intestine from T cell-mediated enteropathy. Gut injury induced by T cell activation is increased in Glp1r-/- and Glp2r-/- mice, as well as in mice with selective loss of intestinal proglucagon gene expression (GcgGut-/-). Conversely, the GLP-2R agonist teduglutide and the GLP-1R agonist semaglutide, administered separately or together, attenuate αCD3-induced intestinal damage in GcgGut-/- mice. Collectively, these findings demonstrate distinct biological roles for endogenous GLP-1R/GLP-2R activity in immune-mediated intestinal injury and highlight the therapeutic potential of glucagon-like peptides, alone or together, for ameliorating T cell-mediated mucosal injury.

Polyendocrine metabolic ovarian syndrome (PMOS) is a leading cause of anovulatory infertility. Although follicular developmental arrest is a defining feature of PMOS, the cell-type-specific mechanisms linking genetic susceptibility, endocrine imbalance and follicular microenvironmental dysfunction remain incompletely understood, particularly across clinical subtypes. We performed single-cell RNA sequencing of preovulatory follicular-fluid cells from healthy controls and women with uncomplicated PMOS, hyperandrogenic PMOS and metformin-treated insulin-resistant PMOS. We integrated these data with GWAS-derived disease relevance scores and ovarian chromatin-accessibility annotations to map genetic risk to follicular cell populations and regulatory programmes. Ligand-receptor analyses were used to infer intercellular communication networks. Transcriptomic metabolic findings were further assessed by follicular-fluid metabolic and steroid-hormone measurements, DHT-treated granulosa-cell functional assays, and reanalysis of a DHEA-induced mouse PMOS-like ovarian dataset. We generated a single-cell atlas of the PMOS follicular microenvironment comprising 220,983 high-quality cells. Granulosa cells showed the strongest enrichment of PMOS-related genetic risk, with regulatory-genetic support from ovarian snATAC-seq integration. Among granulosa cell states, a GC2_CYP19A1⁺ population was preferentially associated with hyperandrogenic PMOS and displayed a transcriptional programme characterized by steroidogenic remodelling coupled to reduced energy-metabolic activity. Biochemical profiling supported this endocrine-metabolic imbalance, showing increased follicular-fluid androstenedione (ASD) and estrone, reduced estradiol and E2/ASD ratio, decreased ATP, citrate and fumarate hydratase activity, and increased lactate and β-hydroxybutyrate. Prolonged DHT exposure impaired granulosa-cell mitochondrial respiration, ATP production and mitochondrial membrane potential. In parallel, PMOS subtypes showed immune remodelling and altered ligand-receptor signalling, with hyperandrogenic PMOS associated with increased inflammatory signalling and reduced homeostatic or tissue-repair pathways. Reanalysis of a DHEA-induced mouse ovarian dataset provided supportive evidence for androgen-associated steroidogenic pathway perturbation. This study provides a cell-resolved framework linking PMOS genetic susceptibility to endocrine-metabolic and immune remodelling in the preovulatory follicular microenvironment. The identification of a hyperandrogen-associated GC2_CYP19A1⁺ state highlights a candidate cellular programme in which steroidogenic imbalance is coupled to impaired granulosa-cell bioenergetics. These findings provide a resource for future validation and may inform microenvironment-guided stratification of PMOS and the development of strategies aimed at restoring follicular function.

This retrospective study examined whether long-term SGLT-2i use is associated with differences in thyroid-stimulating hormone (TSH) and the systemic immune-inflammation index (SII) in patients with type 2 diabetes mellitus (T2DM) without known thyroid disease. The neutrophil-to-lymphocyte ratio (NLR), renal function (eGFR), diabetes duration, and metformin use were also evaluated as potential covariates. This was a single-center, retrospective observational study. Adults with T2DM who had used empagliflozin or dapagliflozin for at least six months were compared with an age- and sex-matched control group of patients with T2DM not using SGLT-2i, drawn from the same outpatient clinics. Key exclusion criteria included known thyroid disease, known positivity for thyroid autoantibodies, active inflammatory or autoimmune processes, advanced organ failure, and immunomodulatory treatment. TSH, SII, and NLR were measured. Statistical analyses included intergroup comparisons, correlation, multivariate linear regression, post-hoc power calculation, and multicollinearity diagnostics (variance inflation factor, VIF). The study included 330 patients across the empagliflozin (n = 139), dapagliflozin (n = 85), and control (n = 106) groups. Median TSH (1.6, 1.8, and 1.9 µIU/mL; p = 0.338) and SII (481, 531, and 468.5; p = 0.509) did not differ significantly between groups. SII and NLR were significantly correlated (r = 0.467, p < 0.001). In multivariate regression, female sex (B = 0.161, p = 0.015) and eGFR (B=-0.0043, p = 0.037) were independent predictors of log-transformed TSH; SGLT-2i use, SII, NLR, age, metformin use, and diabetes duration were not. The study had 80% power to detect a Cohen's f of 0.17 or greater; observed effect sizes were substantially below this threshold (f = 0.02 for TSH, f ≈ 0.00 for SII). Long-term SGLT-2i use was not associated with significant changes in TSH or SII in patients with T2DM without known thyroid disease, and the achieved effect sizes suggest that any true effect, if present, is likely small. Renal function emerged as an independent correlate of TSH, suggesting that the relationship between the hypothalamic-pituitary-thyroid axis and renal physiology merits further attention in this population, independent of SGLT-2i exposure. Prospective, multicenter studies incorporating free thyroxine and triiodothyronine measurements are warranted to further clarify these relationships. This study is retrospective and does not involve a clinical trial registration.

Copyright: &copy; 2026 El-Deiry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The WIN Consortium International Molecular Tumor Board brings together precision oncology experts from 18 organizations in 13 countries across four continents and provides discussion for patients with cancer across the world. This case report details the medical journey of a 55-year-old man diagnosed with high-grade glioblastoma (GBM), characterized by amplifications of MDM2 and EGFR, alongside other critical genomic alterations, including a CDKN2A frameshift mutation. Despite the aggressive nature of GBM, the patient was in remission following a combination of radiotherapy and chemotherapy, surgery and participation in a phase II clinical trial (PI3K/mTOR inhibitor) combined with ketogenic diet and metformin. However, the patient was also considering personalized neoantigen vaccine therapy targeting tumor-specific mutated peptides as part of his treatment strategy. This case underscores the immense complexity of treating GBM. Next generation sequencing showed MDM2 amplification, which hinders the tumor-suppressive functions of p53, and EGFR amplification, which promotes oncogenic signaling. The experts highlighted various therapeutic options discussed in the event of relapse: EGFR inhibitors, various MDM2 inhibitors, and personalized combination therapies targeting both EGFR and CDK4/6. Additionally, the Molecular Tumor Board discussed the reported risk of resistance or hyper-progression with immune checkpoint blockade in the presence of EGFR and MDM2 alterations. Innovative approaches such as combining MDM2 and EGFR inhibitors with immunotherapy, as well as the use of teserpaturev, a genetically engineered herpes simplex virus were addressed. This case emphasizes the importance of personalized treatment strategies for GBM and the need for ongoing clinical research to explore novel therapeutic options.

Metformin is a well-established treatment for Type 2 diabetes. Beyond its role in glycemic control, metformin has gained attention for its pleiotropic effects, including cardioprotective properties. However, its role in autoimmune myocarditis and subsequent postinflammatory dilated cardiomyopathy remains poorly understood. To investigate the role of metformin in autoimmune-mediated cardiac disease, we employed the experimental autoimmune myocarditis mouse model. Six to eight weeks old Balb/c mice were immunized twice with an α-myosin heavy chain peptide emulsified in complete Freund's adjuvant to induce myocarditis and progression toward dilated cardiomyopathy. Metformin was administered in two approaches: a preventive (from Days 0 to 21 or 40) and a therapeutic (from Days 21 to 40). Cardiac function and disease progression were evaluated at two time points: Day 21 (inflammatory phase) and Day 40 (fibrotic phase), using echocardiography, histopathological assessment, and molecular analyses. Treatment with metformin resulted in activation of the AMP-activated protein kinase-dependent signaling pathway during the inflammatory phase of myocarditis. This treatment was associated with activation of apoptosis-related pathways and a moderate reduction in inflammatory cell infiltration. Mice receiving metformin in the preventive approach exhibited preserved cardiac function. This was accompanied by decreased cardiomyocyte cross-sectional area and altered expression of hypertrophy-associated genes (Acta1 and Myh6). In contrast, neither preventive nor therapeutic administration of metformin significantly reduced the extent of myocardial fibrosis. Our findings suggest that metformin provides cardioprotective effects during the early inflammatory stages of autoimmune myocarditis and, to a lesser extent, during the later fibrotic remodeling phase. Untreated acute myocarditis can lead to functional decline and postinflammatory dilated cardiomyopathy. Using an autoimmune myocarditis mouse model, we demonstrate that preventive metformin treatment reduces cardiac inflammation and preserves cardiac function. These findings suggest that metformin, in addition to its applications in diabetes, could be used to prevent inflammatory heart disease.

Pregnancy is characterized by physiologic, metabolic, immunologic, and microbial adaptation. Medication use during pregnancy is common. Yet, therapeutic response often remains unpredictable because obstetric pharmacology has historically focused on pharmacokinetic changes while paying little attention to host-microbiome-drug interactions. Pharmacomicrobiomics, the study of bidirectional interactions between the microbiome and therapeutic agents, has emerged as an important frontier in precision medicine. Increasing evidence demonstrates that the maternal microbiome may influence drug bioavailability, metabolism, efficacy, toxicity, immune response, and placental signaling during pregnancy. Conversely, medications used in obstetric practice, including antibiotics, antiretrovirals, metformin, iron supplementation, and proton pump inhibitors, may reshape maternal microbial ecosystems with downstream implications for maternal-fetal health. Pregnancy introduces pharmacomicrobiomic complexity because the maternal gut, vaginal, and oral microbial communities evolve across gestation, while the placenta and fetus are exposed to microbial metabolites and microbe-associated signals without convincing evidence of stable resident microbiomes. Emerging data suggest that microbial composition may influence preterm birth, hypertensive disorders of pregnancy, gestational diabetes mellitus, obesity, fetal growth, immune development, and therapeutic responsiveness. This mini-review examines recent advances in obstetric pharmacomicrobiomics with emphasis on microbial regulation of drug metabolism, pregnancy-associated microbial remodeling, microbiome-mediated therapeutic variability, placental and fetal implications, and future translational applications. We propose that obstetric pharmacology is entering a systems biology era in which the maternal microbiome should be investigated as a potentially important determinant of therapeutic response rather than treated solely as a background physiologic variable. Integrating microbiome science into maternal-fetal therapeutics may ultimately improve individualized treatment strategies, drug development, and precision obstetric pharmacology.

Glycolytic metabolism of tumor cells suppresses the activity of immune cells, and multiple blocking energy supply and remodeling the metabolic microenvironment are important strategies to enhance immunotherapy. Using manganese-doped porphyrin metal-organic framework (MOF) as a carrier, by depositing ultrasmall Au nanoparticle (AuNPs), loading metformin (MET) and coating polydopamine (PDA), an integrated MOF@Au/MET@PDA nanozyme with multi-enzyme activity was constructed for enhancing antitumor immunotherapy. MOF@Au/MET@PDA nanozyme possessed glutathione peroxidase/glucose oxidase/peroxidase/catalase-like activity, by which the reactive oxygen species generation was greatly enhanced, and the mitochondrial function was damaged. Moreover, by consuming glucose and inhibiting the synthesis of adenosine triphosphate, the MOF@Au/MET@PDA nanozyme effectively blocked the energy supply and hindered glycolysis. Furthermore, the MOF@Au/MET@PDA nanozyme up-regulated the Caspase 3/7 level and down-regulated the expression of programmed death ligand-1, by which the apoptosis was induced and the immunogenic cell death was triggered. Under the combined immunotherapy, the immune response was activated, and the primary and metastatic tumors were greatly inhibited, proving the strong immune effect of MOF@Au/MET@PDA nanozyme. STATEMENT OF SIGNIFICANCE: Tumor metabolic plasticity undermines the efficacy of single-pathway immunotherapy. In this work, a multi-enzymatic MOF@Au/MET@PDA nanozyme is engineered to mediate metabolic reprogramming by blocking energy supply through glucose depletion and suppression of glycolysis/oxidative phosphorylation. It amplifies oxidative stress, triggers ICD, down-regulates PD-L1, and remodels the immunosuppressive microenvironment. This nanozyme effectively inhibits primary breast tumors and lung metastasis, providing a metabolic-reprogramming strategy to boost tumor immunotherapy.

Although neoadjuvant therapy has achieved higher levels of resectability and improved the survival outcomes of pancreatic carcinoma patients, cancer cells' resistance to conventional cell death has limited its clinical efficiency. Thus, developing an optimal sequence of novel neoadjuvant therapy modalities to boost cancer cell death is urgently needed. The current work addresses this issue by developing a combination of radiotherapy with metformin as a novel neoadjuvant therapy and investigating its optimal sequencing treatment to boost cancer cell ferroptosis. Of the three treatment regimens investigated, the sequential treatment with RT followed by metformin (i.e. as opposed to metformin followed by RT, or simultaneous treatment with both RT and metformin) was most effective in eliciting ferroptosis in vitro and in animal models. Mechanically, RT followed by metformin is dependent on the inhibition of the AMPK-GOT1 axis, which further leads to the arrest of cancer cells in G1/S phase, and ultimately ferroptosis. Moreover, using a combination of patient samples and mouse models, RT followed by metformin enhanced the anti-tumor immune cells (IFNγ+CD8+T cells, DC cells, and M1 macrophage) infiltration and cytokines (IFN-γ and IL-2) level, inhibited the pro-tumor immune cells (PD-1+TIM3+ CD8+T cells and M2 macrophage) infiltration and cytokines (TGF-β and IL-10) level. Overall, the study developed an optimal sequencing of neoadjuvant therapy modality that induced superior cancer cell ferroptosis and boosted anti-tumor immunity, which presented a promising therapeutic approach for refractory tumors.

Central nervous system (CNS) diseases impose a substantial global burden; however, effective treatments remain limited. Neuroinflammation contributes to the development and progression of various CNS diseases. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may alleviate neuroinflammation by modulating immune cell-related processes, showing therapeutic potential in CNS diseases. We searched PubMed/MEDLINE, Embase, and Web of Science for literature published between 2016 and 2026. We summarize preclinical evidence that various GLP-1RAs alleviate neuroinflammation across different CNS diseases through modulation of peripheral and central immune cells, focusing on neutrophils, monocytes/macrophages, T lymphocytes, microglia, astrocytes, and their crosstalk, and discuss related clinical translation and challenges. Repurposing GLP-1RAs, including exenatide, liraglutide, semaglutide, and dulaglutide, may provide a therapeutic option for CNS diseases. However, most mechanistic evidence remains preclinical, and clinical efficacy has not been established. Future studies should integrate neuroimmune biomarkers with clinical outcomes to determine whether immunomodulatory effects translate into clinical benefit. Future research should also distinguish direct CNS effects from peripheral metabolic effects across different GLP-1RAs and identify appropriate patient populations. The effects of age, sex, comorbidities, and concomitant medications on efficacy and safety, as well as potential adverse effects of long-term use, also warrant attention.

Giant cell arteritis (GCA) is a large-vessel vasculitis predominantly affecting individuals over 50 years, with a peak incidence between 70 and 80 years. Its pathogenesis involves complex immunological cascades triggered by vascular dendritic cell activation, recruitment of CD4⁺ T cells and monocytes, T helper lymphocyte polarization, and vascular remodeling driven by myofibroblasts and fibroblasts. Growing evidence implicates cellular senescence (particularly in vascular smooth muscle cells, fibroblasts, endothelial cells, and immune cells) in the pathophysiology of GCA. Senescent cells (SC) accumulate in affected arteries and display a senescence-associated secretory phenotype (SASP), producing pro-inflammatory cytokines, chemokines, and matrix metalloproteinases, thereby perpetuating inflammation and tissue injury. Senotherapeutics (agents targeting SC) are broadly classified into senolytics, which induce SC apoptosis, and senomorphics, which suppress SASP without eliminating SC. Candidate senolytics include fisetin, quercetin, curcumin, and dasatinib, which also show anti-inflammatory, antioxidant, and vascular-protective effects, although some may cause adverse vascular consequences. Senomorphics such as resveratrol, kaempferol, apigenin, epigallocatechin gallate, rapamycin, metformin, and ruxolitinib modulate NF‑κB, mTOR, JAK/STAT, and sirtuin pathways, potentially reducing vascular inflammation, restoring immune balance, and preventing remodeling, besides acting on aging-associated modifications. As current treatments primarily suppress inflammation and may not fully target age-related mechanisms contributing to persistent vascular injury, investigating cellular senescence as a potentially actionable component of GCA biology is timely. Key challenges include selecting optimal agents, timing, dosing, and duration, while avoiding adverse vascular effects. The aim of this review was to identify potential clinical and translational applications of senotherapeutic compounds for GCA to guide future research in this field.

This study investigates the cooperative antitumor potential of combining metronomic cyclophosphamide (MTm-CTX) with the metabolic modifier metformin (MET) in a murine model of mammary carcinoma. While metronomic chemotherapy offers a reduced toxicity profile, its efficacy as a monotherapy is often limited by compensatory inflammatory signaling. We hypothesized that metabolic intervention with metformin could sensitize tumor cells to metronomic dosing by modulating key survival and immune pathways. Using mice bearing Ehrlich solid carcinoma (ESC), we evaluated the effects of MTm-CTX and MET, both individually and in combination, on tumor progression and the underlying molecular landscape. Our results demonstrate that the combination therapy significantly inhibits tumor growth, achieving a marked 65% reduction in tumor volume compared to the control group. Mechanistically, the combined regimen was associated with an apoptotic shift, characterized by the upregulation of p53 and the significant downregulation of survivin and Ki-67 expression. Furthermore, the treatment effectively modulated the tumor microenvironment by suppressing NF-κB, TNF-α, and IL-6 expression. Notably, this local tumor suppression is coupled with enhanced systemic cytotoxic immunity, marked by a significant upregulation of splenic Granzyme B alongside a numerical upward trend in interferon-gamma (IFN-γ) expression. Quantitative histopathological analysis confirmed substantial tumor regression and reduced viability in the combination group. These findings provide compelling evidence that the MTm-CTX and MET combination acts through a coordinated alternation of apoptotic and immune-inflammatory pathways. This study establishes a scientifically grounded framework for a potentially promising, cost-effective, and low-toxicity chemo-metabolic strategy worthy of further exploration in breast cancer management.

The bone marrow (BM) microenvironment is increasingly recognized as a dynamic immunometabolic niche that critically governs hematologic malignancies and BM-associated disorders, including acute myeloid leukemia (AML), multiple myeloma, myelodysplastic syndromes (MDS), metastatic infiltration, and aplastic anemia. At the core of this ecosystem, hematopoietic and leukemic stem cells (HSCs/LSCs) undergo profound immunometabolic reprogramming driven by complex interactions with stromal and immune components. Mesenchymal stromal cells (MSCs) enhance mitochondrial fitness and oxidative phosphorylation (OXPHOS) in malignant cells via cysteine supply and mitochondrial transfer, while endothelial cells regulate niche retention and survival through CXCL12 and adhesion molecules such as E-selectin. Adipocytes further support tumor bioenergetics by supplying free fatty acids (FFAs) that fuel fatty acid oxidation (FAO), whereas M2-polarized macrophages reinforce immunosuppressive and metabolic adaptations through arginase-1 activity and FAO-dependent pathways. These coordinated interactions promote a metabolically flexible phenotype characterized by shifts between OXPHOS and glycolysis, activation of FAO and glutamine metabolism, and engagement of one-carbon metabolism, collectively sustaining malignant progression. Concurrently, the BM niche establishes a profoundly immunosuppressive milieu mediated by myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), indoleamine 2,3-dioxygenase 1 (IDO1)-driven kynurenine signaling, lactate-induced acidosis, and HIF-1α-mediated pseudo-hypoxia, which together impair anti-tumor immunity and facilitate disease persistence. Importantly, these immunometabolic dependencies provide actionable therapeutic vulnerabilities. Targeted strategies, including IDH1/2 inhibitors (ivosidenib and enasidenib), BCL-2 inhibition (venetoclax), niche-disrupting agents (plerixafor and uproleselan), OXPHOS inhibitors (IACS-010759 and metformin), and immunometabolic interventions such as IDO1 inhibitors and CAR-T therapies represent emerging precision approaches. Collectively, this integrative framework highlights the BM microenvironment as a central regulator of cancer cell metabolism and immune evasion, underscoring the potential of immunometabolic targeting to overcome therapeutic resistance and enable next-generation precision medicine in hematologic diseases.

The GLP-1 receptor agonist semaglutide preserves kidney function in people with type 2 diabetes and chronic kidney disease, but the underlying mechanisms are unclear. Here we report a 52-week randomized trial of subcutaneous semaglutide 1 mg once weekly versus placebo (n = 106 (n = 25 women, n = 81 men)) in participants with type 2 diabetes and chronic kidney disease. To identify kidney-specific mechanisms of action for semaglutide, we performed integrated multiparametric magnetic resonance imaging of the kidney and biopsy for histology (n = 33), alongside single-nucleus (n = 22) and spatial transcriptomics (n = 13) on paired samples with before- and after-treatment measurements. Coprimary magnetic resonance imaging outcomes (oxygenation by R2*, global perfusion and tissue inflammation by T1 mapping) were not significantly altered by semaglutide versus placebo treatment. Secondary outcomes revealed that semaglutide treatment, as compared to placebo, was associated with a significantly reduced renal artery resistive index and stabilization of the apparent diffusion coefficient, indicating prevention of fibrosis progression. Moreover, secondary transcriptomic outcomes revealed pronounced effects of semaglutide on glomerular endothelial cells, consistent with the results of spatial analyses indicating reduced numbers of immune cells in the proximity of these endothelial cells. The results from this trial indicate that mechanisms of kidney protection by semaglutide may include reduced vascular resistance, prevention of fibrosis and improved underlying molecular programs promoting endothelial cell health. ClinicalTrials.gov identifier: NCT04865770 .

Chronic inflammation underlies several common diseases although it is inadequately managed by conventional anti-inflammatory therapies that often suppress immune responses and have long-term adverse effects. Innate immune memory encompasses trained immunity and tolerance, which provide a comprehensive framework for persistent maladaptive innate responses that drive the pathogenesis of neurodegenerative disorders, oncological, cardiometabolic, and autoimmune diseases. This Invited Mini-Review elucidates the molecular mechanisms of innate immune memory including epigenetic reprogramming of chromatin configurations, metabolic rewiring towards glycolytic or oxidative metabolic pathways and the signaling of pattern recognition receptors (PRRs) and the NLRP3 inflammasome that reinforce either enhanced or diminished innate responsiveness. We subsequently discuss pharmacological strategies for selective modulation of innate immune memory. Epigenetic modulators including histone deacetylase (HDAC) and Bromodomain and Extra- Terminal Domain (BET) inhibitors may modify aberrant chromatin programs, while metabolic modulators like metformin and statins can influence their cellular bioenergetics and inflammatory response. Direct NLRP3 inflammasome inhibitors including MCC950 and INF-39 target maladaptive NLRP3 inflammasome signaling. MCC 950 was stopped at the preclinical stage due to hepatotoxicity. Early clinical studies of trained immunity include Bacillus Calmette-Guerin (BCG) vaccine and metabolic modulation. These studies provide evidence that innate immunity programming can be altered in humans, but clinical disease modifying efficacy has not yet been established. We examine translational obstacles and provide a strategy for precision immunopharmacology that incorporates molecular biomarkers, cell-type- and disease-specific targeting, and combinatorial methods to achieve selective immune reprogramming. The development of targeted modulators for innate immune memory will require robust biomarker frameworks. Such approaches may provide more effective and durable therapeutic advances for chronic inflammatory disorders while reducing global immunosuppression.

Painful diabetic neuropathy (PDN) involves metabolic, inflammatory, and neuroimmune disturbances. Quercetin may alleviate diabetic neuropathy, but the associated gut-spinal mechanisms remain unclear. To investigate whether quercetin improves PDN in association with gut microbial remodeling, spinal betaine-related metabolism, and magnetic resonance imaging-derived spinal gadopentetate dimeglumine signal dynamics. A two-stage study combined quercetin intervention, antibiotic-associated gut perturbation, multi-omics analyses, and independent betaine validation in a diet/streptozotocin-induced rat model of PDN. PDN rats received quercetin (30 or 60 mg/kg) or metformin. The 60 mg/kg dose was also evaluated during antibiotic co-treatment. Behavioral, metabolic, histological, inflammatory, oxidative-stress, immunofluorescence, western blot, fecal metagenomic, targeted spinal metabolomic, and magnetic resonance imaging assessments were performed. A separate cohort received intraperitoneal betaine. Quercetin improved pain hypersensitivity, metabolic dysfunction, intestinal barrier-associated readouts, inflammation, spinal oxidative stress, magnetic resonance imaging-derived gadopentetate dimeglumine signal dynamics, and the overlap between aquaporin-4 and glial fibrillary acidic protein, with stronger overall effects at 60 mg/kg. Antibiotic co-treatment attenuated several quercetin-associated effects. Multi-omics analyses highlighted betaine-related metabolic changes, while exploratory protein changes related to the spinal choline-betaine metabolic branch were attenuated by antibiotics. Betaine partially reproduced selected downstream effects and was accompanied by lower exploratory inflammatory-pathway protein readouts. Quercetin alleviated PDN and was associated with coordinated gut, systemic, and spinal changes. Betaine may represent one candidate functional contributor, although microbiota-specific causality and the directionality of the proposed gut-spinal connection remain unestablished.

Autoimmune polyglandular syndromes (APS) are a rare group of disorders characterized by the dysfunction of multiple endocrine and non-endocrine organs due to autoimmune destruction. APS type 3B (APS3B) is a subtype characterized by the coexistence of autoimmune thyroiditis and pernicious anemia, more commonly observed among middle-aged females. Here, we describe a unique case, workup, and diagnosis of APS3B in a 58-year-old Hispanic male who presented with an atypical presentation of APS3B complicated by metformin use and possible transfusional iron overload. Workup revealed positive intrinsic factor antibodies and elevated homocysteine and methylmalonic acid levels, confirming pernicious anemia. Thyroid studies demonstrated markedly positive anti-thyroid peroxidase antibodies and elevated thyroid-stimulating hormone, consistent with autoimmune thyroiditis. He was treated with blood transfusions, initiation of intramuscular vitamin B12 injections, and discontinuation of metformin. This case highlights how APS may be overlooked in patients with multiple chronic comorbid conditions and should be considered in those presenting with several endocrine abnormalities.

Photothermal therapy (PTT) has emerged as a promising antitumor modality; however, the inflammatory response triggered by PTT promotes the infiltration and activation of immune cells within the tumor microenvironment, leading to elevated IFN-γ secretion. This inflammatory cytokine subsequently upregulates PD-L1 on tumor cells, facilitating tumor immune evasion and limiting the long-term efficacy of PTT. To address these challenges, we engineered a living platform (PMEA) by coating Escherichia coli Nissle 1917(ECN)with a polydopamine-metformin(MET) layer and incorporating a heat-inducible azurin circuit. Critically, we employed a two-step thermal regimen: a mild pre-heating phase (42 °C) to trigger robust azurin production and accumulation within the tumor core, followed immediately by a medium-power ablation phase (≥45 °C). During the ablation phase, the accumulated azurin exerts an apoptotic effect on tumor cells and disrupts mitochondrial integrity, synergizing with PTT to enhance the therapeutic efficacy. Consequently, the synergistic interplay between photothermal heat and azurin-induced mitochondrial dysfunction achieves enhanced immediate tumoricidal efficiency, while the PDA@MET layer concurrently suppresses PTT driven PD-L1 upregulation. In a CT26 model, this synergistic regimen achieved >80% inhibition and significantly extended survival, providing a paradigm for spatiotemporally programmable bacteria-based combination therapy.

Chemotherapy-induced toxicity remains a major cause of treatment discontinuation, reduced quality of life, and long-term morbidity in cancer survivors. Established chemoprotective agents (dexrazoxane, mesna, and amifostine) are limited by narrow indications (dexrazoxane: only anthracycline cardiotoxicity), significant adverse effects (amifostine: hypotension in 62%), and lack of efficacy against common toxicities such as peripheral neuropathy. This focused review evaluates emerging chemoprotective strategies with preclinical or early clinical data published between 2015 and 2025, with an emphasis on agents that address unmet clinical needs. This is a critical narrative review, not a systematic review. A literature search was conducted in PubMed, Scopus, and ClinicalTrials.gov (2015-2025) using keywords including "chemoprotection," "nanoparticle," "curcumin," "resveratrol," "dual COX-2/TNF-α inhibitor," "Nrf2 modulator," and "chemotherapy-induced peripheral neuropathy." Articles were selected based on relevance to chemoprotection, mechanistic clarity, and availability of preclinical or clinical data. Three major emerging categories were identified: (i) Nanoformulated natural products such as curcumin, resveratrol, luteolin, and naringenin encapsulated in polymeric, lipid, or cyclodextrin-based nanocarriers, demonstrate improved bioavailability and enhanced efficacy in preclinical models though chemoprotection-specific clinical data remain limited (ii) Dual COX-2/TNF-α inhibitors (e.g., NO-donating aspirin). simultaneously suppress inflammatory and oncogenic signaling (NF-κB, β-catenin, STAT3) and have shown polyp burden reduction in familial adenomatous polyposis, though cardiovascular safety concerns persist. (iii) Nrf2 pathway modulators, including sulforaphane (activator) and brusatol (inhibitor), present a paradox: activation protects normal tissues but may also shield tumors. Physical strategies (limb hypothermia) and repurposed drugs (metformin) offer additional avenues but need Phase III validation. Emerging mechanistic frontiers including ferroptosis inhibition, pyroptosis modulation, and neuroimmune targeting represent additional promising directions. Nanoformulation is the most technologically mature strategy for overcoming bioavailability barriers. Dual inhibitors offer pleiotropic benefits but require safer designs. Nrf2 modulators demand careful patient stratification. Future trials must incorporate biomarker-driven enrollment and standardized chemoprotection endpoints. Comparative analysis across categories reveals that strategies with simpler mechanisms and well-defined surrogate endpoints have advanced furthest clinically, highlighting the importance of rigorous trial design and validated biomarkers for successful translation.

This narrative review synthesizes current evidence on immunometabolic interactions in gynecologic cancers, with emphasis on their implications for tumor biology, therapeutic response, and global cancer care. Emerging data indicate that systemic metabolic dysfunction is closely integrated with tumor microenvironment immune remodeling. Key features include enhanced glycolysis, nutrient competition, lipid accumulation, and hypoxia, which collectively impair cytotoxic T-cell function, promote immune exhaustion, and support immunosuppressive myeloid phenotypes.Although gynecologic malignancies share common immunometabolic hallmarks, distinct tumor-specific patterns are evident. Cervical cancer is characterized by human papillomavirus-associated metabolic reprogramming and immune checkpoint activation; ovarian cancer demonstrates dependence on lipid metabolism and omental adipose interactions; and endometrial cancer is strongly associated with obesity-driven insulin resistance and endocrine-inflammatory signaling. This review evaluates potential biomarkers and therapeutic strategies, including metformin, statins, and immune checkpoint inhibitor-based combinations, and clearly distinguishes between preclinical findings and clinically established interventions. Current evidence for metabolic targeting remains largely exploratory, with variable degrees of clinical validation across tumor types. In addition, this review highlights implementation challenges in low- and middle-income countries, particularly limited access to advanced molecular diagnostics and immunotherapies, and discusses opportunities for scalable, low-cost metabolic approaches. Finally, we outline future research priorities, including spatial multiomics, longitudinal metabolic profiling, and computational modeling approaches to improve patient stratification and predictive accuracy. Overall, immunometabolism represents a promising but evolving framework for improving understanding and management of gynecologic cancers, with important implications for both precision oncology and global health equity.