Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals used in a variety of consumer and industrial applications for their water- and oil-resistant properties. Firefighters can be exposed to PFAS as part of their job through gear, aqueous film-forming foams (AFFFs) used to extinguish aircraft and liquid fuel fires, along with exposure through other combustible materials during fire suppression activities. PFAS exposure has been linked to a variety of health conditions including cancer, obesity, reproductive issues, and immunosuppression. Epigenetic modifications may be one mechanism underlying PFAS toxicity. In this study, we used epigenetic indicators to assess association of PFAS serum concentrations with (1) epigenetic aging and (2) DNA methylation at loci within genes related to immune function. Blood leukocyte DNA methylation was quantified via the Infinium EPIC array from 184 participants in the Fire Fighter Cancer Cohort Study involved in aircraft rescue and firefighting, and serum PFAS was measured via on-line solid phase extraction liquid chromatography isotope dilution tandem mass spectrometry. We observed inverse associations between PFAS concentrations and epigenetic clocks including between serum linear perfluorooctanoic acid (n-PFOA) with four epigenetic clocks (p < 0.05); however, most did not remain significant in sensitivity analyses. Associations (q < 0.1) were observed between perfluorodecanoic acid, n-PFOA, sum of branched perfluorooctane sulfonic acid isomers and differential methylation of specific loci within 34 immune-related genes. Further research can help to better understand the functional impacts of the observed differential methylation on immune health.

Lymphocyte activation gene 3 (LAG3) protein is a key immune inhibitory checkpoint receptor that suppresses T cell activation, proliferation and effector functions to maintain immune homeostasis and tolerance. In persistent pathological settings, chronic T cell receptor (TCR) signalling, together with sustained LAG3 signalling and other inhibitory receptor signalling, drives T cell dysfunction, highlighting LAG3 as a promising therapeutic target. However, more than 30 years after its discovery, the fundamental mechanisms governing LAG3 signalling and function remain incompletely defined. Elucidating LAG3 downstream signalling pathways and the mechanisms of action of LAG3-blocking antibodies is essential for identifying optimal clinical indications, developing predictive biomarkers, designing more effective LAG3-targeted therapeutics and maximizing clinical efficacy. Recent advances have revealed key molecular mechanisms, including constitutive tonic signalling, ligand-induced ubiquitination-dependent signalling switches and LAG3-TCR proximity-mediated suppression. In this Review, we comprehensively examine LAG3 signalling mechanisms, synthesize current understanding of its functional effect on T cells, discuss emerging therapeutics and their mechanisms of action, and evaluate biomarker strategies for patient selection. We conclude by highlighting key challenges and outlining future directions for LAG3-targeted immunotherapy in oncology and autoimmune disease.

This study aims to characterize systemic and colonic intestinal mucosal immune phenotype in dairy cows across the periparturient period, and to determine whether Saccharomyces cerevisiae boulardii CNCM I-1079 (SCB) supplementation affects those components. Holstein cows (n = 83) were blocked by parity and randomly assigned to either control (CON; n = 43) or SCB (n = 40; targeted supplementation: 1.0 × 10[10] cfu/cow/d of SCB top dressed) dietary treatments from d -28 prepartum to d 70 postpartum. Blood samples were collected on d -30, -7, 7, 21 and 70 relative to calving and colon biopsies at d -30, 7 and 70. Peripheral blood mononuclear cells (PBMCs) and intraepithelial leukocytes (IELs) were isolated from blood and colon biopsies, respectively, and analyzed by flow cytometry to assess T and B cell subsets, macrophages and dendritic cells. Pre and postpartum data were analyzed separately using linear mixed effect models, with fixed effects of treatment, day and its interaction, and the random effect of cow within block, and day -30 as covariable. Independent of treatment, several myeloid and lymphoid populations changed during early lactation. In blood, the proportion of CD4[+] T cells declined from d 7 to d 21 and then recovered by d 70, whereas CD28 expression on CD4[+] T cells peaked at d 7 and subsequently decreased, indicating early transient activation. Cytotoxic CD8[+] T cells increased in proportion from d 7 to d 21 and remained elevated through d 70. Class-switched (IgG[+]) B cells progressively upregulated CD21 expression from d 7 through d 70, suggesting maturation and enhanced complement-responsiveness later in lactation. Within the colonic intestinal mucosa, dendritic cells were most abundant at d 7, consistent with heightened early postpartum antigen presentation. Supplementation with SCB selectively enhanced humoral activation postpartum, reflected by increased CD86 expression on both naïve (IgM[+]) and class-switched (IgG[+]) B cells. Together, these findings indicate that immune changes during the periparturient period reflect a transient immune activation at immediate postpartum rather than overall suppression, and that SCB supplementation may enhance B cell activation and support immune function during early lactation.

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.

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality, while acquired resistance to EGFR-targeted therapy and an immunosuppressive tumor microenvironment continue to limit therapeutic efficacy. Here, we developed a tumor cell membrane-coated, acid-degradable hollow calcium-manganese nanoplatform loaded with gefitinib (CM@HCC-Mn/Gef) for combined redox modulation and antitumor immune activation. Under acidic and redox-active conditions, CM@HCC-Mn/Gef released gefitinib, Ca[2+], and Mn[2+], leading to intracellular Ca[2+] accumulation, mitochondrial depolarization, ATP depletion, reactive oxygen species generation, glutathione consumption, GPX4 downregulation, and lipid peroxidation. These coordinated effects induced ferroptosis-associated oxidative damage and immunogenic cell death (ICD), characterized by cell-surface calreticulin exposure and HMGB1 redistribution, and subsequently promoted dendritic cell maturation and T-cell activation. In gefitinib-resistant NSCLC cells, CM@HCC-Mn/Gef produced substantially greater cytotoxicity than free gefitinib, indicating that multimechanistic stress amplification enhanced the therapeutic response of resistant tumor cells. In immunocompetent syngeneic LLC tumor models, the nanoplatform inhibited primary tumor growth, increased tumor-infiltrating T cells, alleviated immunosuppressive features of the tumor microenvironment, and delayed contralateral secondary tumor progression. Combination with anti-PD-1 further enhanced tumor suppression and systemic immune activation. Collectively, CM@HCC-Mn/Gef integrates targeted drug delivery, calcium-associated mitochondrial stress, redox disruption, ferroptosis-associated damage, and immune activation, providing a biomimetic nanotherapeutic strategy for NSCLC chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Conventional nanocarriers often provide drug delivery without coordinating multiple tumor-specific stresses and immune activation. This study introduces a tumor cell membrane-coated, acid-degradable hollow calcium-manganese nanoplatform that co-releases gefitinib, Ca[2+], and Mn[2+] in the tumor microenvironment. The material couples calcium-associated mitochondrial dysfunction with manganese-driven redox catalysis, thereby enhancing oxidative damage, lipid peroxidation, and immunogenic cell death-associated responses. It also improves tumor accumulation, promotes dendritic cell maturation and T-cell activation, and enhances anti-PD-1 therapy in immunocompetent lung cancer models. This work establishes a direct link between biomaterial composition, stimulus-responsive degradation, catalytic function, and antitumor immunity, offering a versatile design strategy for biomaterials-enabled chemoimmunotherapy.

Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure used widely for the treatment of unresectable hepatocellular carcinoma (HCC). However, embolization-induced hypoxia upregulates VEGF, and the resulting angiogenic response contributes to tumor recurrence, further limiting the efficacy of TACE against HCC. Herein, we present a multifunctional embolic microsphere system in which sorafenib (SRF) and calcium carbonate (CaCO3) nanoparticles are rationally encapsulated within sodium hyaluronate microspheres (SRF-CaCO3@SH MSs) via microfluidic technology. The microspheres exhibited a bowl-shaped morphology with tunable diameters, which enhances in vivo embolic stability through mechanical interlocking between adjacent microspheres. In an acidic tumor microenvironment (TME), pH-triggered release of Ca[2+] (23.9%) and SRF (65.7%) far exceeded neutral conditions. SRF-CaCO3@SH MSs maintained >85% HUVEC viability and reduced VX2 cell viability to 24.3%, showing maximal cytotoxicity under acidic conditions. After intra-arterial injection, the microspheres occluded tumor-feeding arteries; Ca[2+] released in the acidic TME inhibited angiogenesis, and CaCO3 neutralized TME acidity, counteracting immunosuppression. In a rabbit VX2 orthotopic HCC model, DSA-guided TACE achieved effective occlusion, slowest tumor growth, largest necrosis, and marked downregulation of CD31, Ki67, and VEGF, without systemic toxicity. Combining morphological design, pH-responsive occlusion, TME neutralization, and anti-angiogenesis, this embolic system synergistically enhances TACE and shows strong clinical potential. STATEMENT OF SIGNIFICANCE: Conventional liver cancer embolization frequently fails due to hypoxia-driven angiogenesis and subsequent tumor recurrence. We developed a dual-functional embolic microsphere (SRF-CaCO3@SH MS) that integrates stable vascular occlusion with active modulation of the tumor microenvironment. Utilizing microfluidics, we fabricated bowl-shaped sodium hyaluronate microspheres that mechanically interlock to ensure durable embolization. Under acidic tumor conditions, calcium carbonate neutralizes pH and releases Ca[2+], which synergizes with sorafenib to inhibit angiogenesis and induce apoptosis. In a rabbit orthotopic HCC model, this system demonstrated superior tumor control and necrosis without inducing systemic toxicity. This work presents a microenvironment-responsive embolization strategy integrating durable vascular occlusion, pH modulation, and anti-angiogenic therapy.

Renal candidal bezoar is a rare cause of obstructive pyonephrosis and usually occurs in patients with diabetes mellitus, immunosuppression, urinary obstruction, or indwelling urinary devices. We report an 88-year-old man with type 2 diabetes treated with dapagliflozin, stage 3 chronic kidney disease, and a history of ureteral stricture managed with ureteral stenting who developed recurrent candidal pyonephrosis and extensive fungal bezoar involving the ureter and renal pelvis. Initial treatment at a referring hospital included percutaneous nephrostomy drainage, fluconazole therapy, ureteroscopic ureterotomy, and ureteral stent placement. The patient re-presented with fever and pyonephrosis and was presented to our emergency department. Dapagliflozin was discontinued, the ureteral stent was exchanged, and fluconazole with short course flucytosine was administered pending susceptibility testing. Cultures confirmed fluconazole-susceptible Candida albicans. Staged ureteroscopic debridement using forceps and aspiration achieved complete clearance, followed by renal functional recovery and clinical resolution. This case highlights the need to reassess medication-associated glycosuria, indwelling stent exposure, and mechanical source control in refractory upper-tract candidal bezoar. A review of reported cases suggests that drainage and antifungal therapy are essential, but active endoscopic, percutaneous, or surgical removal is frequently required when organized fungal material persists.

Concurrent chromosomal 17q-gain and MYCN amplification define a subset of neuroblastoma associated with particularly adverse clinical outcomes. However, how these genetic alterations synergize to promote tumor progression and whether their cooperation confers therapeutic vulnerabilities remain elusive. We herein performed a CRISPR-based functional screen targeting 17q-gain genes and identified the RNA m[6]A reader IGF2BP1 as a critical MYCN collaborator to promote aggressive neuroblastomas via activation of phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a key enzyme involved in de novo purine biosynthesis. Rewiring of PAICS-mediated nucleotide metabolism enabled tumor cells to sustain necessary purine pools for productive transcription of replicative stress-responsive genes, including CHK1, to cope with the exacerbated replication stress. Pharmacological inhibition of CHK1 elicited a robust immune reprogramming, leading to activation of cGAS-STING signaling, upregulation of Major Histocompatibility Complex class I expression, and synergistic tumor suppression with immune checkpoint blockade. Altogether, we identify an IGF2BP1/MYCN-PAICS-CHK1 axis that drives aggressive neuroblastoma phenotypes and constitutes an actionable vulnerability for therapeutic intervention.

The present study aimed to investigate the expression and roles of peroxiredoxin 1 (PRDX1) and glutathione (GSH) peroxidase 4 (GPX4) in ferroptosis regulation and the tumor microenvironment in hepatocellular carcinoma (HCC). The expression levels of PRDX1 and GPX4 were assessed in HCC through analysis of datasets from The Cancer Genome Atlas (TCGA), GSE14520 from the Gene Expression Omnibus database and the Human Protein Atlas, along with HCC cell lines. Diagnostic and prognostic values were evaluated using receiver operating characteristic curves and Kaplan-Meier survival analyses. The single-cell dataset GSE149614 was employed to investigate the cellular localization and characteristics of specific cell subpopulations expressing PRDX1 or GPX4 within the HCC tumor microenvironment. The relationships between PRDX1, GPX4 and ferroptosis-related pathways were explored using the FerrDb database and Gene Set Enrichment Analysis. Additionally, their interactions with the immune microenvironment were examined utilizing the CIBERSORT algorithm. To validate the results of the bioinformatics analysis, the present study utilized small interfering (si)RNA technology to construct single gene knockdown and dual gene co-knockdown models targeting PRDX1 and GPX4 in Hep3B cells. Subsequently, the proliferative activity of each group of cells was evaluated using the Cell Counting Kit-8 method and the levels of the intracellular lipid peroxidation product malondialdehyde (MDA) were detected using the MDA detection kit. The results of the present study demonstrated that the expression levels of PRDX1 and GPX4 were upregulated in HCC tissues and cell lines. The area under the curve for the combined diagnostic model of PRDX1 and GPX4 in HCC was 0.83. Furthermore, elevated expression levels of PRDX1 or GPX4 predicted reduced overall survival (OS), and their expression was weakly positively correlated in HCC. Single-cell transcriptomics demonstrated predominant expression of both genes in malignant cells. GPX4 was primarily detected in early-differentiation subgroups enriched in metabolic and ferroptosis pathways, whereas PRDX1 was predominantly expressed in intermediate-differentiation subgroups associated with antioxidative stress pathways. The dual-high PRDX1/GPX4 expression group exhibited increased reactive oxygen species, GSH and iron levels, whereas the dual-low group had prolonged OS. Immune infiltration analysis indicated a trend of higher M0 macrophage levels and lower CD4[+] T-cell counts in the dual-high expression group. Furthermore, PRDX1 expression was positively correlated with multiple immune checkpoint genes, whereas GPX4 expression was markedly negatively correlated only with CD274 and TIGIT. The siRNA-PRDX-1/siRNA-GPX4-1 group exhibited significantly inhibited HCC cell proliferation and promoted MDA production; however, proliferative activity was partially increased compared with that in the siRNA-PRDX-1 group, whereas the levels of MDA accumulation were significantly reduced compared with in the siRNA-GPX4-1 group. In conclusion, the current study revealed the concerted co-expression of PRDX1 and GPX4 in malignant HCC, which was associated with ferroptosis evasion and immune suppression. Furthermore, the present findings suggested that PRDX1 may shift from an antioxidant to a pro-oxidant mediator under GPX4 deficiency, thereby alleviating lipid peroxidation. These findings support targeting this axis as a future therapeutic breakthrough.

Programmed cell death ligand 1 (PD-L1) antibody has been shown to hold tremendous promise in curing metastatic colorectal cancer (CRC). However, the delivery efficacy of the targeted biologics limits this immunotherapy in a subset of CRC. Here we report a novel biomimetic 'Trojan horse' nano-delivery system for targeted gene-immunotherapy of colorectal cancer. The system comprises a core of gold nanoparticles and cationic liposomes encapsulating CRISPR/Cas9-sgSOX9, camouflaged with homologous CRC cell membranes for immune evasion and tumor tropism, and functionalized with PD-L1 antibodies to enhance tumor recognition and relieve immune suppression. In vitro, the nano-system potently suppressed CRC cell proliferation, migration and invasion. in vivo, it exhibited robust tumor-targeting specificity, favorable preliminary biosafety profile and marked inhibition of tumor growth in subcutaneous xenograft models. Mechanistically, the system remodeled the tumor microenvironment by promoting CD8[+] T-cell infiltration and elevating effector cytokines IFN-γ and TNF-α. By seamlessly coupling precise gene delivery with potent immune activation, this nanoplatform offers a compelling therapeutic strategy for colorectal cancer therapy.

BACKGROUND Plasmablastic lymphoma (PBL) is a rare, aggressive large B-cell lymphoma associated with immunosuppression. In Crohn's disease, it can mimic disease exacerbation or infection. We describe a rapidly enlarging intra-abdominal plasmablastic neoplasm in a medically complex patient, emphasizing diagnostic vigilance without inferring a causal association with biological therapy. CASE REPORT A 44-year-old woman with severe fistulizing Crohn's disease treated sequentially with adalimumab, infliximab, and ustekinumab developed progressive systemic deterioration despite partial intestinal stabilization. Her course included portal hypertension secondary to portal vein thrombosis, refractory ascites, severe malnutrition, and recurrent systemic and multidrug-resistant infections. In September 2023 imaging showed a rapidly enlarging intra-abdominal/pelvic mass measuring more than 22 cm. Core-needle biopsy demonstrated a plasmablastic neoplasm positive for CD38, CD138, MUM1, and c-MYC, with equivocal CD10 and negative CD45, favoring PBL. Epstein-Barr virus-encoded RNA in situ hybridization, CD20, PAX5, Ki-67, anaplastic lymphoma kinase, human herpesvirus 8, and tissue light-chain restriction were unavailable. Bone marrow examination, serum and urine immunofixation, complete monoclonal-protein assessment, and whole-body skeletal imaging were not performed; therefore, plasmablastic myeloma could not be definitively excluded. Intensive chemotherapy was not feasible because her Eastern Cooperative Oncology Group performance status was at least 3 and she had multiorgan dysfunction, severe malnutrition, and active infections. The patient was transitioned to palliative care and subsequently died. CONCLUSIONS Discordance between apparent intestinal control and systemic deterioration should prompt urgent tissue diagnosis. The findings favor PBL within the spectrum of plasmablastic neoplasms but neither establish drug-specific causation nor definitively exclude plasmablastic myeloma.