Search Results (1,602)

Pancreatic ductal adenocarcinoma (PDAC) resists checkpoint blockades outside uncommon molecularly selected populations. This narrative review relates clinical combination studies to four overlapping resistance mechanisms: deficient antigenicity, presentation and priming; restricted effector-cell access; suppressive myeloid and regulatory-cell programs; and T-cell dysfunction. The grouping is an organizing heuristic, not a validated treatment-selection algorithm. A source audit through 5 September 2026 reconciled a nonexhaustive inventory of 85 supplied study/cohort entries and relevant additional reports; 84 inventory entries remain in the synthesis after the exclusion of 1 trial. Trial design, endpoint success, component attribution and pharmacodynamic evidence were assessed separately. PA.7 and CISPD3 did not improve their primary survival endpoints when checkpoint blockade was added to chemotherapy. Positive or apparently favorable findings require design-specific interpretation: NASCA changed several components, KG4/2015 pooled randomized and nonrandomized controls, and early vaccine signals have not established a routine benefit. POLAR did not meet its co-primary activity criteria; preliminary SWOG S2001 results did not demonstrate benefits from adding pembrolizumab to olaparib. dMMR/MSI-H remains an established tumor-agnostic selection biomarker, while exploratory PA.7 and tissue-state signatures require independent validation. Human immune changes, immunogenicity and target engagement should not be equated with clinical efficacy. Future trials should test defined component contributions, appropriate pharmacodynamic hypotheses and patient-reported outcomes, with sampling adapted to disease setting and feasibility. Full article

Recurrent pregnancy loss (RPL), a multifactorial condition in reproductive medicine, affects approximately 1–3% of couples. Increasing evidence implicates endometrial dysfunction, immune dysregulation, impaired angiogenesis, and oxidative stress (OS) in its pathophysiology, highlighting the need for biologically targeted therapeutic strategies. In this context, platelet-rich plasma (PRP) has emerged as a regenerative approach with the potential to modulate these underlying mechanisms. This narrative review critically evaluates the biological rationale and current clinical evidence supporting PRP as an adjunctive treatment for RPL while proposing a precision medicine framework for biologically guided patient selection. A comprehensive narrative synthesis of the literature was performed, focusing on studies investigating PRP in RPL and related reproductive conditions, including thin endometrium and recurrent implantation failure (RIF). Mechanistically, PRP promotes angiogenesis through vascular endothelial growth factor (VEGF)-mediated pathways, enhances endometrial regeneration by stimulating stromal and epithelial cell proliferation, and modulates immune responses by promoting regulatory T-cell activity while attenuating pro-inflammatory signaling. In addition, PRP-derived extracellular vesicles (EVs) and microRNAs may contribute to the post-transcriptional and epigenetic regulation of implantation-related genes, including leukemia inhibitory factor (LIF) and HOXA10. Clinical studies in RIF and thin endometrium populations suggest that PRP may improve endometrial thickness, implantation, and clinical pregnancy outcomes; however, these findings constitute indirect evidence for RPL. Direct RPL-specific evidence remains very limited and is insufficient to establish a reduction in miscarriage or an improvement in live birth. These biological features instead provide a rationale for investigating PRP in defined patient subgroups characterized by impaired endometrial receptivity, defective angiogenesis, immune dysregulation, or unexplained RPL with suspected endometrial dysfunction. Accordingly, we propose that future clinical investigation of PRP should move beyond empirical use toward biomarker-informed, precision reproductive medicine strategies. Although PRP represents a biologically plausible and promising adjunctive therapy, robust randomized controlled trials incorporating standardized PRP protocols and biologically stratified patient populations are required before its routine clinical use can be recommended. Full article

Cardiovascular toxicity is an important complication of treatment for hematologic malignancies, but it is often discussed mainly in terms of direct myocardial injury. Endothelial injury may provide a common link between several cardiovascular complications seen in these patients. Endothelial dysfunction may already be present because of the malignancy itself and can be further increased by anticancer treatment, immune activation and haematopoietic stem cell transplantation. Oxidative stress, reduced nitric oxide availability, inflammation, increased vascular permeability and activation of coagulation can shift the endothelium from a protective to a pro-inflammatory and prothrombotic state. These changes could contribute to hypertension, thrombosis, atherosclerotic disease, coronary microvascular dysfunction, arterial stiffness and myocardial dysfunction. The role of endothelial injury is particularly relevant with BCR-ABL inhibitors, proteasome inhibitors, CAR-T-cell therapy, bispecific antibodies and transplantation, although the mechanisms and strength of evidence differ between treatments. Several circulating biomarkers and tools, including angiopoietin-2, von Willebrand factor, soluble thrombomodulin, adhesion molecules and the Endothelial Activation and Stress Index, may help identify endothelial injury, but their clinical roles still remain unclear. This review examines endothelial injury across hematologic malignancies and their treatments and discusses its role in cardiovascular toxicity, current approaches to vascular protection and the main gaps that need to be addressed before endothelial assessment can become part of routine cardio-oncology care. Full article

Since 2020, billions of doses of COVID-19 messenger RNA (mRNA) lipid nanoparticle vaccines have been administered worldwide, generating one of the largest pharmacovigilance databases for a modern therapeutic class. Intriguingly, their immunopharmacologic profile—including the engagement of innate nucleic acid sensors, systemic type I interferon signaling, dendritic cell-mediated cross-priming of CD8+ T cells, and upregulation of programmed cell death ligand 1 (PD-L1)—may extend beyond COVID-19 prophylaxis. Retrospective evidence from six independent cohorts, one of which is a multinational health-data network, indicated that vaccination within 100 days of immune checkpoint inhibitor (ICI) initiation may improve survival of patients with malignancies, including in immunologically cold tumors, although a substantial fraction of the original effect may be attributed to pandemic-era selection bias. Here, we examine the mechanistic basis and available evidence for the repurposing of licensed COVID-19 mRNA vaccines as antigen-agnostic immunomodulators. We identified five candidate contexts for prospective evaluation—namely, (1) PD-L1-negative non-small cell lung cancer initiating ICI therapy, (2) perioperative immune dysfunction in major cardiac surgery, (3) chronic hepatitis B, (4) chronic HIV with persistent immune exhaustion, and (5) sepsis-induced immunoparalysis. Methodological foundations for confirmatory assessment—comprising target trial emulation, Mendelian randomization, and pragmatic trial design—are now sufficiently developed to enable implementation. Prospective evaluation of the antigen-agnostic repurposing hypothesis is operationally feasible, albeit constrained by residual confounding and uncertainty about the durability of vaccine-induced innate reprogramming. Full article

Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer, but resistance and recurrence remain major clinical challenges. Tumor immune–metabolic reprogramming profoundly affects treatment response and immune evasion; however, the molecular mechanisms of lipid metabolism remodeling and its interaction with T cells after CCRT in cervical cancer are still unclear. This study aimed to investigate how CCRT-induced metabolic changes in cervical cancer cells influence T cell function and immune evasion. Methods: We performed metabolic pathway activity analysis, cell–cell communication prediction, and transcriptomic analysis on paired single-cell transcriptomic data from three cervical cancer patients before and after CCRT (n = 3 paired). Validation was conducted using multiple independent GEO cohorts, in vitro cell culture experiments, and multi-sample immunofluorescence staining. Results: CCRT was associated with upregulation of FABP4/5 in malignant epithelial cells and activation of the PPAR and adipocytokine signaling pathways, leading to lipid metabolic reprogramming. Epithelial cells with high FABP4/5 expression showed enhanced predicted intercellular communication with T cells via the computationally inferred ligand–receptor axes PTGER4 and CXCR4. T cells with high communication intensity exhibited an immunosuppressive phenotype signature, accompanied by metabolic alterations in lipid and carbohydrate pathways and enrichment of regulatory T cell subsets. Validation experiments confirmed the association between FABP4/5 and inhibitory T cells. Conclusions: This study suggests that FABP4/5-mediated lipid metabolism reprogramming may represent a key mechanism contributing to the immunosuppressive crosstalk between cervical cancer epithelial cells and T cells after CCRT. Targeting this axis may reverse T cell dysfunction and provide a potential immunometabolic strategy to reduce post-CCRT recurrence. Full article

Type 2 diabetes mellitus (T2DM) is a major global health challenge, with insulin resistance (IR) and islet dysfunction as its core pathophysiology. Current glucose-lowering agents, including insulin secretagogues, insulin sensitizers, DPP–IV inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists, effectively control blood glucose and may partly improve β-cell function indirectly, but they do not directly target the functional defects of pancreatic β cells. Developing drugs that precisely modulate islet function is therefore a key direction. Natural products, with their structural diversity, established glucose-lowering activity, and derivation from medicinal plants with long clinical use, have become an important source of lead compounds for drugs targeting these mechanisms. The main pathways through which natural products act include: (1) promoting insulin secretion through direct and indirect secretagogue mechanisms (modulating ion channels, metabolic enzymes, incretin signaling); (2) preserving β-cell function and mass by maintaining the differentiated phenotype, promoting regeneration, alleviating oxidative stress, inhibiting apoptosis and pyroptosis, attenuating inflammation, and suppressing hIAPP toxic aggregation and endoplasmic reticulum stress; and (3) other pathways with incompletely elucidated mechanisms that also contribute to islet protection. This article delineates these molecular mechanisms and highlights the limited ability of current agents to directly restore and protect β-cell function. It provides a theoretical basis for developing novel drugs that integrate glycemic control with islet restoration based on natural lead compounds, and offers a framework for further mechanistic studies. In addition, it encourages the exploration of unidentified active constituents and unique pathways, while also addressing challenges such as target identification and structure–activity relationships. Full article

Cervical, ovarian, and endometrial cancers comprise biologically distinct malignancies with substantial heterogeneity in their molecular alterations, metabolic dependencies, immune landscapes, and therapeutic responses. Despite advances in surgery, chemotherapy, radiotherapy, targeted therapies, and immunotherapy, these cancers remain major causes of cancer-related morbidity and mortality worldwide. Signal Transducer and Activator of Transcription 3 (STAT3) is frequently activated in these tumor types, where its biological and clinical relevance varies according to disease context, histological subtype, and molecular characteristics. In addition to tumor-intrinsic functions regulating proliferation, survival, angiogenesis, and stemness, STAT3 participates in dynamic interactions between malignant cells and the tumor microenvironment (TME), integrating inflammatory, metabolic, and stromal signals. Persistent STAT3 activation has been associated with immunosuppressive changes involving macrophage polarization, myeloid-derived suppressor cell expansion, dendritic cell dysfunction, regulatory T-cell accumulation, and impaired cytotoxic lymphocyte activity, although the extent and mechanisms of these effects differ among tumor types and experimental contexts. Metabolic alterations, including enhanced glycolysis, lactate accumulation, and hypoxia, may further interact with STAT3-dependent signaling and influence communication between tumor and stromal or immune compartments. In this review, we examine STAT3 as a signaling node linking tumor metabolism with immune regulation in cervical, ovarian, and endometrial cancers, while emphasizing disease- and subtype-specific differences. We summarize current evidence on STAT3-mediated tumor–microenvironment communication and discuss emerging STAT3-targeted therapeutic strategies. Finally, we highlight challenges related to biological heterogeneity, the lack of validated predictive biomarkers, and patient stratification that currently limit the clinical translation of STAT3-directed approaches. Full article

Gastrointestinal (GI) malignancies account for approximately one-quarter of new cancer diagnoses and more than one-third of cancer-related deaths worldwide, yet as of August 2026, only one CAR-T therapy has received regulatory approval for a solid tumor indication anywhere in the world. The recent CT041-ST-01 phase II trial of satricabtagene autoleucel, the first randomized CAR-T trial conducted in a solid tumor, demonstrated a significant improvement in progression-free survival for patients with advanced gastric cancer (median 3.25 vs. 1.77 months; hazard ratio (HR) 0.37, p < 0.001). While this landmark study established the clinical feasibility of CAR-T therapy in solid tumors, it also underscored the biological barriers that continue to limit durable responses. GI tumors are characterized by heterogeneous antigen expression, dense desmoplastic stroma, inefficient immune-cell trafficking, profoundly immunosuppressive tumor microenvironments, and progressive T-cell dysfunction, all of which are further compounded by the logistical and economic challenges of autologous cell manufacturing. In this narrative review, we organize these obstacles within a unified four-barrier engineering framework and critically examine the strategies being developed to overcome each of them. We discuss advances in multi-antigen and logic-gated CAR architectures, stromal remodeling through fibroblast activation protein (FAP)-targeted approaches and extracellular matrix-degrading enzymes, chemokine receptor engineering, regional delivery, hypoxia-responsive CARs, cytokine-armored and persistence-enhanced constructs, dominant-negative and switch receptors, metabolic reprogramming, and intrinsic checkpoint disruption. We also review emerging manufacturing platforms, including allogeneic CAR-T and CAR-natural killer (CAR-NK) cells, induced pluripotent stem cell-derived products, CAR-macrophages, and in vivo CAR generation, together with engineering strategies designed to improve safety and scalability. Rather than relying on a single technological advance, the future of CAR-based therapy for GI malignancies will likely depend on integrating multiple engineering approaches to address the diverse biological barriers within the tumor microenvironment. By synthesizing current preclinical and early clinical evidence, this review provides a translational framework for the next generation of CAR-based cellular therapies in gastrointestinal oncology. Full article

Background/Objectives: Osteoarthritis (OA) is strongly associated with mitochondrial dysfunction, oxidative stress, and the accumulation of mitochondrial DNA (mtDNA) alterations in several joint-associated cell types, including chondrocytes, synoviocytes, and mesenchymal stromal cells (MSCs). These alterations contribute to impaired cellular homeostasis and reduced regenerative potential. In this study, we systematically characterized mtDNA heteroplasmy and variant distribution across bone marrow MSCs, induced pluripotent stem cells (iPSCs) and induced MSCs (iMSCs) derived from OA patients and healthy donors. Methods: Ultra-deep mitochondrial genome sequencing was integrated with transcriptomic and miRNome analyses to investigate mitochondrial remodeling during cellular reprogramming, encompassing changes in mtDNA heteroplasmy, variant distribution, mtDNA copy number and associated transcriptomic adaptations of nuclear-encoded mitochondrial pathways. Results: OA-derived MSCs exhibited a markedly increased heteroplasmic burden, followed by decrease in mtDNA copy number and accumulation of non-synonymous variants, particularly within OXPHOS-related genes, including MT-ND1-5, MT-ATP8, MT-CO1, and MT-RNR1/2. Reprogramming into iPSCs and subsequent differentiation into iMSCs were associated with an increase in mtDNA copy number and a progressive reduction in heteroplasmic variants predicted to have pathogenic potential, including m.7913C>T and m.7821G>A, as well as substantial reduction in heteroplasmic variant burden within several mitochondrial genes, suggesting mitochondrial genome remodeling during cellular reprogramming. Multiomic analysis further revealed coordinated deregulation of mitochondrial-associated nuclear genes and ceRNA regulatory networks involving lncRNAs MEG3 and SNHG14, along with multiple mitochondria-related miRNAs. These findings suggest post-transcriptional regulations associated with mitochondrial adaptation in iMSCs Conclusion: Collectively, our findings suggest that cellular reprogramming is associated with mitochondrial genomic reorganization in the donor-matched cell populations examined. These exploratory observations support the utility of iMSCs as a relevant model for studying OA-associated mitochondrial alterations and as a potential tool for regenerative approaches in OA. Full article

Obesity has become a major global public health concern, with prevalence rates rising dramatically over the past several decades and affecting more than one billion people worldwide. The increasing burden of obesity has been largely driven by sedentary lifestyles and the consumption of energy-dense, nutrient-poor diets, although its etiology is multifactorial, involving complex interactions among genetic, metabolic, endocrine, and environmental factors. Beyond excess adiposity, obesity is closely associated with numerous chronic diseases, including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), hypertension, cancer, and chronic inflammatory disorders. Emerging evidence indicates that oxidative stress plays a pivotal role in the pathogenesis of obesity and its related metabolic complications. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), which are generated during normal cellular metabolism, serve important physiological functions in cell signaling and redox regulation. However, excessive production of these reactive species or impairment of endogenous antioxidant defense systems disrupts redox homeostasis, leading to oxidative damage to lipids, proteins, and nucleic acids. Such alterations contribute to cellular dysfunction, chronic inflammation, and disease progression. In this context, dietary antioxidants have attracted considerable attention due to their ability to neutralize free radicals, inhibit lipid peroxidation, and restore redox balance. Natural antioxidants derived from fruits, vegetables, and other plant-based foods may act individually or synergistically to enhance cellular defense mechanisms against oxidative stress. Furthermore, growing evidence suggests that antioxidant-rich dietary patterns may offer protective effects against obesity-associated metabolic disturbances and chronic diseases. However, clinical benefits of isolated antioxidant supplementation remain inconsistent and appear to depend on dose, bioavailability, baseline redox status, disease stage, and the preservation of physiological redox signaling. Understanding the molecular mechanisms underlying antioxidant-mediated regulation of redox homeostasis may facilitate the development of nutritional strategies for obesity prevention and management, while contributing to the reduction in oxidative stress and obesity-related disease burden and the promotion of long-term health. Full article

Recent advances in cutaneous neuroimmunology have substantially expanded our understanding of inflammatory skin diseases, revealing an intricate bidirectional network linking peripheral sensory neurons, resident immune cells, and structural skin components. Among the mediators orchestrating this communication, substance P (SP) and mast cells have emerged as pivotal regulators connecting neuronal activation with immune responses, vascular dysfunction, chronic inflammation, and persistent pruritus. Beyond the canonical neurokinin-1 receptor (NK1R), the identification of the Mas-related G protein-coupled receptor X2 (MRGPRX2) has fundamentally reshaped mast-cell biology by establishing an IgE-independent pathway of neuropeptide-induced activation. This narrative review examines the molecular mechanisms underlying the mast cell–SP neuroimmune axis and discusses its contribution to the pathogenesis of allergic contact dermatitis and atopic dermatitis. Unlike the traditional approach, which primarily considers atopic dermatitis as the reference model for cutaneous neuroimmune interactions, allergic contact dermatitis may provide a useful model for examining how neuroimmune amplification integrates with delayed T-cell-mediated inflammation. These concepts are subsequently applied to atopic dermatitis, where they operate within the broader context of type 2 inflammation, epidermal barrier dysfunction, and chronic pruritus. Rather than replacing classical immunopathogenic models, this emerging neuroimmune perspective complements them by identifying bidirectional communication between sensory neurons and mast cells as a dynamic amplifier of adaptive immune responses. This integrated perspective not only provides a unifying interpretation of inflammatory dermatitis but also offers a conceptual basis for exploring similar neuroimmune mechanisms across other immune-mediated skin disorders and for generating future mechanism-based therapeutic hypotheses. Full article

Type 2 diabetes (T2D) is increasingly understood as a chronic, low-grade inflammatory disease in which immune and metabolic signalling are bidirectionally coupled. Nutrient excess drives glucolipotoxic stress in adipose tissue, liver, skeletal muscle and pancreatic islets, engaging innate immune sensors. Responding immune cells then reconfigure their own intermediary metabolism, and the resulting metabolites—succinate, which stabilises hypoxia-inducible factor-1α, and the itaconate that opposes it—themselves specify inflammatory output. These signals converge on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, gasdermin D-mediated pyroptosis and interleukin-1β (IL-1β) release, which interrupt insulin signalling through inhibitory serine phosphorylation of insulin receptor substrate-1. Mitochondrial dysfunction, impaired mitophagy and cytosolic mitochondrial DNA sensing sustain the loop, while gut barrier failure supplies a parallel systemic input that converges on beta-cell dysfunction. This narrative review synthesises these mechanisms and examines how metformin, glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter 2 inhibitors and inflammasome-directed agents intersect with them. The chain described is that of obesity-associated T2D, and the heterogeneity that limits its generalisation across the recognised subgroups of the disease is addressed explicitly rather than assumed away. We give particular weight to a dissociation that constrains the field: sustained IL-1β neutralisation reduced cardiovascular events without preventing incident diabetes. Establishing why is, in our view, the central question for immunometabolic therapeutics in T2D. Full article

Background/Objectives: Despite effective antiretroviral therapy, cancer remains a relevant comorbidity in people living with HIV (PLWH), with an increasing burden of non-AIDS-defining cancers (NADCs). We assessed cancer prevalence and systemic inflammation using a composite score based on routine inflammatory biomarkers. Methods: We conducted a retrospective cross-sectional study of PLWH in Ferrara, Italy. Cancer history, immunovirological parameters, IL-6, CRP, D-dimer, and monocyte counts were collected. A composite inflammatory score (0–4) was derived from biomarker abnormalities and compared between AIDS-defining cancers (ADCs) and NADCs. Results: Among 566 participants, 64 had a history of cancer (11.3%; 95% CI, 8.7–13.9%), accounting for 79 diagnoses: 23 (29.1%) ADCs and 56 (70.9%) NADCs. Most diagnoses (82.3%) were associated with inflammatory scores of 0–1, whereas 17.7% had scores of 2–4, with similar distributions between ADCs and NADCs (17.4% vs. 17.9%; p = 0.962). D-dimer elevation was more frequent among NADCs than ADCs (42.9% vs. 21.7%). Higher inflammatory scores were significantly associated with lower current CD4+ T-cell counts (p = 0.043). Conclusions: Cancer was a substantial comorbidity among PLWH, with NADCs predominating despite favorable immunovirological status. The composite score integrated routinely available inflammatory, coagulation, and immune parameters, with higher scores associated with lower CD4+ counts. Although inflammatory profiles did not differ significantly between ADCs and NADCs, this finding highlights the complexity of immune dysregulation in PLWH and the limitations of individual circulating biomarkers. Further validation of composite inflammatory scores may provide a clinically accessible framework for characterizing residual immune dysfunction and its relationship with cancer development and outcomes. Full article

Olfactory dysfunction is an early non-cognitive feature of Alzheimer’s disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and immune cells for studying AD pathobiology. Histopathological and patient-derived culture studies have reported amyloid-β, tau, oxidative-stress, mitochondrial, biometal, and transcriptional abnormalities in olfactory tissue. More recent endoscopically guided brush sampling with single-cell profiling has identified activated memory CD8 T-cell states, inflammatory myeloid programs, and neuronal metabolic changes, including in cognitively unimpaired individuals with abnormal cerebrospinal-fluid amyloid biomarkers. These findings support olfactory-cleft sampling as a research platform for investigating early neural–immune changes, but current evidence is based on small, largely cross-sectional cohorts and does not establish disease specificity, causality, or prognostic utility. Longitudinal multicenter studies integrating olfactory-tissue profiling with established fluid, imaging, genetic, cognitive, and olfactory biomarkers are required before clinical translation. Full article

Background. Immunosuppressive conditioning regimens for chimeric antigen receptor-modified T cell immunotherapy (CARTx) and subsequent T cell dysfunction increase risk for infection. However, it is difficult to discern infection from CRS in the early (up to Day 30) and late (Days 31–180) periods after CARTx due to overlapping signs and symptoms. Methods. We analyzed infectious complications and predictors of infection during the early and late periods after CARTx in 213 adult patients with malignancies over a 5-year period. Results. Overall, 75 patients (35%) had at least one infection, mostly within the first 30 days after CARTx. Infections occurring early after CARTx were mostly bacterial, whereas viral infections predominated after Day 30. In multivariate analyses, a high baseline CRP (≥5 mg/dL) was significantly associated with increased risk of infection in the early period after CARTx, and a Day-5-to-baseline-CRP ratio of <1.5 was significantly associated with a higher risk of infection through all 180 days after CARTx and during the late period after CARTx. Conclusions. Infections in adult patients are common up to 180 days after receiving CARTx. High baseline CRP without significant temporal changes may predict risk of infection. Tracking CRP trends may be a useful clinical tool for discerning causes of fever and guiding antibiotic stewardship in this population at high risk for infections. Full article