Search Results (7,528)

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD⁺ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine–ornithine metabolism, and tryptophan–kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy. Full article

Invasive pulmonary mold infections (IPMIs) are critical complications in immunocompromised patients, contributing significantly to morbidity and mortality. Diagnosing pathogens like Aspergillus species (spp.) and the Mucorales remains challenging due to non-specific clinical presentations and the limitations of traditional culture methods. This review provides an up-to-date synopsis of IPMI diagnostic tools, focusing on their diagnostic performance, turnaround time (TAT), and cost-effectiveness. We conducted a narrative review of the current literature regarding clinical evaluation, radiographic findings, invasive diagnostics, and non-invasive assays, including next-generation sequencing (NGS) and volatile organic compounds (VOCs). Chest computerized tomography (CT) remains a vital first step, though classic signs like the “halo” or “reverse halo” are neither sensitive nor specific. Traditional diagnostics are limited by low sensitivity and delayed results. While plasma microbial cell-free DNA (mcfDNA) NGS offers rapid TAT (24–48 h) and high specificity, its suboptimal sensitivity for Aspergillus spp. (<50%) and high cost remain significant barriers. Investigational VOC “breath tests” show promising sensitivity (77–96%) but lack standardization. Future research must prioritize the standardization of non-invasive microbiologic testing modalities, particularly those with rapid TAT such as bedside “breath tests” and high-throughput mcfDNA NGS. Development of clinical algorithms that balance cost-effectiveness with timely pathogen diagnosis based on the patient’s degree of immunosuppression is essential to improve survival in high-risk populations. Full article

The Hippo, as a central pathway regulating cell proliferation, apoptosis, stem cell homeostasis and organ development, is closely associated with the onset and progression of tumors, metabolic reprogramming, drug resistance and immune evasion when it is abnormally inactivated. The Hippo not only directly promotes tumor cell proliferation, maintains cancer stem cell properties, and mediates metabolic reprogramming and treatment resistance, but also reshapes the tumor microenvironment(TME) by regulating the formation, heterogeneity and function of cancer-associated fibroblasts (CAFs). Furthermore, it mediates tumor immunosuppression and immune evasion by modulating programmed death-ligand 1(PD-L1) expression, T-cell function, macrophage polarization and cytokine secretion. At the same time, inflammatory cytokines, growth factors, metabolites and physical signals within the TME can negatively regulate the activity of the Hippo, creating a pro-tumor positive feedback loop. This article provides a systematic review of the composition and regulation of the Hippo , its mechanisms of action in the biological behavior of tumor cells and interactions within the tumor microenvironment, as well as progress in the development of drugs targeting this pathway. It offers a theoretical basis for a deeper understanding of the role of the Hippo in tumors and for the development of novel anti-tumor therapeutic strategies. Full article

CAR-T cell therapy remains ineffective in most solid tumours because effector cells infiltrate poorly, undergo exhaustion, and face antigen escape within an immunosuppressive microenvironment. To address this, we developed a hybrid framework that combines a mechanistic spatiotemporal model with machine learning for limited individual-level mechanistic personalisation under data constraints. At its core, we employed a reaction–diffusion–chemotaxis model describing functional and exhausted CAR-T cells, antigen-positive and antigen-negative tumour subpopulations, a chemoattractant, an immunosuppressive factor, and hypoxia. Gradient boosting combined with nested cross-validation was used to recover model-consistent latent-parameter pseudo-labels generated by a limited inverse problem. Within this surrogate-target setting, parameters characterising the tumour microenvironment and CAR-T cell exhaustion were reproduced most robustly, whereas antigen escape and individualised initial conditions were substantially less well constrained. As an auxiliary reference point, we also considered a direct empirical baseline for binary clinical outcomes. This baseline indicated that the observed clinical features contained a more stable signal for disease control than for objective response. A favourable response was associated with high CAR-T cell infiltration and cytotoxic potency, whereas resistance was linked to exhaustion, antigen escape, and a suppressive microenvironment. Overall, the proposed approach should be interpreted as an internally validated, hypothesis-generating proof-of-concept platform for mapping clinical features to mechanistically interpretable surrogate latent targets, rather than as evidence for validated recovery of true patient-specific biological parameters. Full article

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibro-inflammatory lesions of the biliary tree. In the absence of available, effective medical therapies, many patients progress to liver failure, making PSC one of the leading indications for liver transplantation (LT), despite its rarity. While LT in PSC is associated with good overall short- and long-term survival, post-transplant outcomes are limited by recurrent PSC (rPSC), which affects up to one quarter of PSC recipients with a significant risk of graft loss and re-transplantation. The risk of rPSC reflects a complex interaction between donor and recipient factors including associated inflammatory bowel disease (IBD), and long-term exposure to immunosuppression. Therefore, post-transplant management requires an individualized multidisciplinary approach and tailored immunosuppressive regimens aimed at balancing the risk of rejection and rPSC with the risk of infection and malignancy. Optimal control of IBD has emerged as a key modifiable determinant of rPSC risk and post-transplant outcomes. In addition, patients with PSC, particularly PSC-IBD patients, carry a significantly increased risk of hepatobiliary and colorectal cancer. Importantly, this oncological risk persists after LT. Thus, long-term, structured cancer surveillance must remain an integral component of post-transplant care. Looking ahead, novel therapies targeting shared hepatic and intestinal fibro-inflammatory pathways are currently being investigated to modify disease activity in the pre-transplant setting. Future studies are needed to assess whether these agents might be applicable also in the post-transplant setting to improve long-term graft and patient survival. Full article

This systematic review examines the emerging interplay between ferroptosis and disulfidptosis, two distinct forms of regulated cell death (RCD) centered on the SLC7A11 (also known as xCT)-mediated metabolic paradox. Traditionally recognized as a potent anti-ferroptotic factor, SLC7A11 imports cystine for glutathione synthesis to neutralize iron-dependent lipid peroxidation. However, the discovery of disulfidptosis identifies SLC7A11 as a metabolic liability, representing a paradigm shift in our understanding of cellular antioxidant defense. This discovery reveals a transformative vulnerability in SLC7A11-overexpressing cells, shifting the focus from conventional survival mechanisms to the consequences of catastrophic structural collapse. Beyond metabolic exhaustion, this review highlights the role of metal dyshomeostasis as a primary driver, spanning from iron-catalyzed ferroptosis to copper-mediated metabolic interference. This conceptual framework redefines the SLC7A11 axis as a targetable “double-edged sword” in therapy-resistant malignancies. Clinical synthesis of multi-omic gene signatures, such as the disulfidptosis- and ferroptosis-related gene prognostic score (DRGPS) and the ferroptosis- and disulfidptosis-related gene (FDRG) scores, demonstrates their robust value in prognostic stratification and in predicting immunotherapy response across malignancies, including lung adenocarcinoma and hepatocellular carcinoma. Furthermore, we evaluate the capacity of disulfidptosis to prime immunogenic cell death (ICD) and remodel the immunosuppressive tumor microenvironment to bypass chemoresistance. By integrating mechanistic insights with clinical data, this review provides a comprehensive framework for targeting the SLC7A11 axis as a transformative therapeutic vulnerability in precision oncology. Full article

Retinoblastoma is the most common intraocular malignancy of childhood and is most often driven by loss of the RB1 tumor suppressor gene. While current treatments achieve high survival rates, they are frequently associated with significant morbidity, highlighting the need for more precise, biology-driven therapeutic methods. Increasing evidence suggests that retinoblastoma progression is not dictated by neoplastic cells alone, but rather by complex interactions within the tumor microenvironment, including stromal and immune components. In this review, we examine the cellular and molecular landscape of retinoblastoma with a particular focus on the immune microenvironment, including the spatial distribution and functional roles of innate and adaptive immune cells, as well as immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4. We discuss how tumor- and treatment-induced immune suppression shapes disease progression and therapeutic response, and how chemotherapy alters immune infiltration and checkpoint expression. Finally, we explore emerging immunotherapeutic and cell-based approaches, emphasizing the potential for combination therapies that integrate immune modulation to improve outcomes and reduce long-term toxicity in retinoblastoma. Full article

The plague, caused by Yersinia pestis, has resulted in significant mortality over the past century. Despite advances in antimicrobial therapy, plague remains a re-emerging infectious disease with ongoing outbreaks and increasing concerns regarding antimicrobial resistance. Today, plague cases are still being reported, and the loss of effectiveness of treatment methods remains a major challenge. Therefore, effective treatment strategies are needed. In this study, we aimed to develop aptamers specific to Yersinia outer protein M (YopM), a key immunosuppressive protein that is essential for virulence. Our goal was to develop an aptamer that binds to YopM and inhibits its interaction with the human DEAD-box helicase 3 (DDX3) protein. YopM-DDX3 protein interaction was targeted because of its key role in nucleocytoplasmic shuttling of YopM. To achieve this, we developed the YopM16 aptamer using magnetic bead-based (Systematic Evolution of Ligands by Exponential Enrichment) (SELEX). The selected YopM16 aptamer exhibited a half-maximal inhibitory concentration(IC₅₀) value of 103.3 ± 2 nM and effectively inhibited the interaction between YopM and DDX3. The inhibitory effect of the aptamer on protein interaction was confirmed using a pull-down assay and colorimetric test. Given that protein–protein interaction surfaces are considered undruggable, YopM16 is a promising inhibitor with the potential to serve as a molecular tool to investigate the virulence mechanism of YopM, as well as a novel antibacterial agent upon validation of its inhibition in cellular models. Full article

Background: Graft-versus-host disease (GVHD) is a common severe complication of allogeneic hematopoietic stem cell transplant. The current treatments are limited by steroid toxicity, broad immunosuppression, and the potential suppression of the graft-versus-tumor (GVT) effect. Developing less toxic therapies is an unmet need. We previously showed that systemically infused negatively charged immune-modifying microparticles (IMPs) composed of carboxylated poly-lactic-co-glycolic acid are taken up by inflammatory monocytes via the MARCO receptor, reducing symptoms and improving survival in inflammatory conditions. We hypothesized that IMPs could reduce acute GVHD manifestations. Methods: Acute GVHD was induced in an MHC-mismatched murine transplant model with radiation conditioning. IMPs were infused for five days; outcomes were compared to saline controls. We assessed organ histopathology, immune cell populations in the spleen and intestine, serum cytokine levels, and the GVT effect. Results: IMP-treated mice showed significant improvements in terms of clinical GVHD scores, histopathology, and survival. They had increased regulatory T-cells in the spleen and intestine and decreased colonic inflammatory monocytes and cytokines such as IL-6 and IFN-γ. IMPs were ineffective in MARCO knockout mice, confirming receptor dependence. Importantly, GVT activity was preserved, as evidenced by improved survival in mice with A20 lymphoma treated with IMPs. Conclusions: Systemic IMPs reduce clinical GVHD signs and improve survival, likely by decreasing inflammatory monocytes via MARCO and expanded regulatory T-cells numbers, while maintaining GVT activity. These findings support further investigation of IMPs as a targeted GVHD therapy. Full article

Background: Eosinophilic granulomatosis with polyangiitis (EGPA), formerly Churg–Strauss syndrome, is a rare necrotizing vasculitis characterized by asthma, eosinophilia, and systemic granulomatosis vasculitis. Perioperative risk is primarily driven by airway hyperreactivity, potential cardiac disease, chronic immunosuppressive therapy, and reported alterations in plasma cholinesterase activity. Evidence specifically addressing anesthetic management remains scarce and largely limited to case-based reports. Methods: A focused narrative review was conducted by searching MEDLINE (via PubMed), Scopus, and Embase from inception to January 2026 for publications reporting perioperative anesthetic management in patients with EGPA/Churg–Strauss syndrome. Case reports and case-based descriptions providing explicit anesthetic details were qualitatively synthesized. Results: Available evidence consists predominantly of isolated case reports across heterogeneous surgical settings, including ENT, abdominal, orthopedic, ambulatory, pediatric, and rare cardiac procedures. Recurring perioperative principles include optimization of bronchial disease and continuation of inhaled therapy; minimization of airway stimulation and avoidance of histamine-releasing drugs; selection of induction agents preserving hemodynamic stability in the presence of myocardial involvement; preference for non-depolarizing neuromuscular blockade with quantitative monitoring (and consideration for sugammadex when appropriate); individualized corticosteroid management and multimodal, opioid-sparing analgesia, often supported by regional techniques. Conclusions: In the absence of dedicated perioperative guidelines, anesthetic care for EGPA should be individualized based on clinical phenotype and organ involvement. A structured approach targeting airway protection, cardiovascular stability, safe neuromuscular management, and opioid-sparing analgesia may represent a pragmatic risk-mitigation framework. These considerations are illustrated by an institutional experience in mitral valve surgery. Full article

Background/Objectives: Herpes zoster is caused by varicella-zoster virus reactivation, which often leads to a chronic pain condition named postherpetic neuralgia (PHN). Patients with immunosuppressive conditions face a heightened risk of developing PHN. This study aims to identify factors contributing to PHN development in immunosuppressive patients. Methods: This retrospective cohort study was conducted involving 219 immunosuppressive patients from two centers and split into training and test cohorts. Participants were divided into PHN (n = 88) and acute phase pain (ACP, n = 131) groups. Univariate and multivariate logistic regression analyses were used to identify clinical predictors of PHN. A nomogram was constructed to predict PHN risk by integrating significant predictors. The discrimination, calibration and clinical usefulness of the nomogram were evaluated. Results: Multivariate analysis revealed metabolic syndrome, older age, higher lactate dehydrogenase (LDH), and higher neutrophil-to-lymphocyte ratio (NLR) as significant PHN predictors. The nomogram showed good discrimination in both training (AUC of 0.83 [95% CI 0.77–0.90] with a specificity of 0.78, sensitivity of 0.87, NPV of 0.90, and PPV of 0.73) and test cohorts (AUC of 0.85 [95% CI 0.75–0.96] with a specificity of 0.82, sensitivity of 0.85, NPV of 0.89, and PPV of 0.76). Clinical decision curve analysis confirmed the practical utility of the nomogram. Conclusions: The nomogram incorporating age, metabolic syndrome, LDH, and NLR are useful in estimating PHN risk among immunosuppressed patients. Full article

Background: Chimeric antigen receptor (CAR) T cells achieve cure in the therapy of hematological malignancies. In solid tumors, however, CAR-T cells face an immunosuppressive tumor microenvironment (TME) which crucially impedes their cytotoxic capacities. Citrate accumulating in the TME is a crucial metabolite in mediating immune suppression and is consumed by cancer cells promoting growth of various tumors, including melanoma; blocking the citrate transporter pmCiC with gluconate abrogates citrate-mediated tumor growth. Methods: To bolster treatment of melanoma, we explored gluconate as adjuvant for CAR-T cell therapy. Results: First, gluconate did not impair CAR-T cell functional capacities with regard to cytotoxicity, cytokine secretion, and persistence in a “stress test” based on repetitive antigen stimulation with cognate cancer cells. The addition of gluconate antagonized the citrate-mediated enhanced proliferation of melanoma cells. As a consequence, the elimination of citrate-boosted melanoma cells by CSPG4-specific CAR-T cells was augmented in the presence of gluconate. Conclusions: Taken together, these data suggest that counteracting citrate-mediated enhanced tumor growth with gluconate may improve the cytotoxic activity of CAR-T cells against melanoma. Full article

Tumor-associated macrophages (TAMs) are pivotal in shaping the immunosuppressive tumor microenvironment (TME). Reprogramming TAMs towards an anti-tumor M1 phenotype represents a promising strategy to enhance anti-tumor immunity. While Fe₃O₄ nanoparticles (NPs) possess immunomodulatory potential, the influence of NP size on macrophage polarization and the underlying mechanisms remain unclear. This study aims to systematically investigate the size-dependent immunomodulatory effects of Fe₃O₄ NPs and elucidate their mechanisms. We synthesized a series of Fe₃O₄ NPs of controlled sizes (5 nm, 10 nm, 30 nm, and 100 nm) via the polyol method. Among these, the 10 nm NPs demonstrated superior cellular uptake efficiency in macrophages. This enhanced uptake induced a significant increase in intracellular reactive oxygen species (ROS) levels. Subsequently, the elevated ROS activated the NF-κB signaling pathway, promoting M1 macrophage polarization. This polarization was evidenced by enhanced CD86 expression, increased nitric oxide (NO) release, and elevated secretion of pro-inflammatory cytokines. This study identifies 10 nm as the optimal size for Fe₃O₄ NPs to elicit their maximal immunomodulatory effects. Our findings establish a crucial size-design principle for the rational development of nano-immunotherapeutic agents and identify 10 nm Fe₃O₄ NPs as a promising candidate for TAM-targeted cancer therapy. Full article

Oncogenic driver mutations in non-small cell lung cancer (NSCLC) activate defined signaling pathways that sustain tumor growth and influence the immune landscape. Yet, how coordinated interactions among diverse cell populations within the tumor immune microenvironment (TIME) contribute to this process remains largely unresolved. To address this, we profiled approximately 200,000 single cells from 45 treatment-naïve NSCLC patients representing seven major driver mutations. This analysis uncovered five multicellular modules (CM1–5) with distinct functional properties, each linked to specific malignant regulatory programs. Among them, CM2 and CM5 exhibited pronounced invasive features and were associated with unfavorable clinical outcomes. CM2 was predominantly observed in EGFR- and MET-driven brain metastases and was defined by strong crosstalk between astrocytes and myofibroblasts. Factors such as SPP1, PTN, and PSAP, together with metabolic alterations, contributed to a microenvironment supportive of metastatic colonization in the brain. By contrast, CM5 was enriched in ROS1-, KRAS-, and EGFR-mutant tumors and consisted of diverse myeloid and endothelial subsets characterized by immunosuppressive and pro-angiogenic signaling, including MIF, GALECTIN, and RETN, collectively facilitating immune escape and vascular remodeling. We further constructed and validated a driver mutation-specific prognostic signature (DMSP.sig) model integrating receptor–ligand interactions and core transcription factors, which effectively stratified patient survival. Leveraging this model, we also identified potential therapeutic candidates linked to these prognostic features, highlighting opportunities for clinical intervention. In summary, our study delineates how oncogenic drivers give rise to distinct TIME architectures, providing a framework for prognostic assessment and precision immunotherapy in high-risk NSCLC. Full article

Introduction: Patients with inflammatory arthritis are at increased risk of infection due to immune dysregulation and immunosuppressive therapy. National and international guidelines recommend vaccination against pneumococcal disease, influenza, COVID-19, and herpes zoster; however, uptake remains inconsistent. This study evaluated op-world uptake of multiple recommended vaccines within a large UK cohort. Methods: We conducted a cross-sectional study of adults with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis across three hospital sites serving ~800,000 people. Eligible patients had a healthcare encounter within 12 months prior to 1 January 2026. Vaccination status (pneumococcal, influenza, COVID-19, shingles) was obtained from linked primary care records. Demographic and clinical variables were collected. Uptake was reported as percentages with 95% confidence intervals. Associations with pneumococcal vaccination were assessed using Poisson regression with robust standard errors. Results: Among 2158 patients (median age 58 years; 72% female), rheumatoid arthritis was most common (61%). Most were receiving biologic or targeted synthetic DMARDs. Vaccine availability was not limited. Uptake was suboptimal: pneumococcal 30%, influenza 29%, COVID-19 53%, and shingles 12%. Pneumococcal uptake was higher in those aged ≥65 years. Increasing age (aRR 1.92, 95% CI 1.52–2.42) and at-risk comorbidities (aRR 1.42, 95% CI 1.20–1.69) were associated with higher uptake, while biologic or targeted therapy was associated with lower uptake (aRR 0.55, 95% CI 0.48–0.63). Discussion: Vaccination uptake remains suboptimal in this high-risk population. Lower uptake in patients on advanced therapies highlights a gap in care. Targeted education and better integration of vaccination pathways within rheumatology services are needed. Full article