BackgroundColorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide. Diet is among the few modifiable determinants of CRC risk, yet the global contribution of specific dietary factors over time, and their projected impact, is not fully understood. Assessing both historical patterns and future trends is essential for guiding prevention strategies.MethodsWe used estimates from the Global Burden of Disease (GBD) 2021 study to quantify CRC mortality, disability-adjusted life years (DALYs), and age-standardized rates (ASRs) attributable to six dietary risk factors across 204 countries and territories from 1990 to 2021. Analyses were stratified by sex, age, sociodemographic index (SDI), and region. We applied decomposition analysis to separate demographic from epidemiological drivers and a Bayesian age-period-cohort (BAPC) model to project ASRs through 2050.ResultsBetween 1990 and 2021, global ASRs for diet-related CRC declined, yet the absolute number of cases rose. In 2021, low whole grain intake (28.38%), low milk intake (24.01%), and high red meat consumption (23.31%) were the leading dietary risks for CRC mortality, with comparable rankings for DALYs. Men, older adults, and high-SDI populations experienced the heaviest burden, while the highest ASRs linked to low calcium intake occurred in low-SDI regions, particularly in Southeast Asia, Africa, the Caribbean, and Oceania. Modelled projections suggest continued global declines in ASRs through 2050, but with slower reductions in high-SDI settings and relatively larger gains in some low- and middle-SDI regions; disparities are unlikely to close.ConclusionAlthough diet-attributable CRC rates have declined, the global burden remains substantial and heterogeneous across SDI strata. Projections to 2050 indicate the need for SDI-tailored prevention strategies, prioritizing reductions in red and processed meat in high-SDI settings and improvements in calcium-related intake in low-SDI regions, supported by context-appropriate dietary guidelines and public health programmes.

ADP-ribosylation factor-like 4 A (ARL4A), a small GTPase involved in cytoskeletal dynamics and signal transduction, exhibits dysregulated expression in various cancers, yet its comprehensive role across tumor types, particularly in thyroid carcinoma (THCA), remains underexplored. This study aimed to perform a systematic pan-cancer analysis of ARL4A to elucidate its expression patterns, prognostic implications, genetic and epigenetic alterations, immune correlations, drug sensitivity, and functional contributions to THCA progression. Leveraging multi-omics data from TCGA and tools including TIMER2.0, GEPIA2, UALCAN, cBioPortal, and LinkedOmics, we evaluated ARL4A across 33 cancer types. Functional validation was conducted by overexpressing ARL4A in THCA cell lines (BCPAP and KTC-1), with assessments via Western blotting, CCK-8 proliferation assays, wound healing, and Transwell migration assays. ARL4A mRNA levels were significantly reduced in tumors such as THCA, correlating with early stages in some cancers but poor overall survival in THCA, adrenocortical carcinoma, and bladder cancer. Genetic amplifications predominated, alongside promoter hypomethylation in multiple malignancies. ARL4A expression inversely correlated with CD8 + T cells and other antitumor infiltrates while positively associating with myeloid-derived suppressor cells and immunosuppressive chemokines. Drug sensitivity analysis revealed negative correlations with HSP90 inhibitors. In THCA cells, ARL4A overexpression enhanced proliferation, migration, and epithelial-mesenchymal transition markers (N-cadherin and Vimentin). These results establish ARL4A as an oncogenic promoter in THCA through modulation of proliferation, migration, and immunosuppressive microenvironments, positioning it as a promising prognostic biomarker and therapeutic target for precision oncology.

Fibronectin type III domain containing 1 (FNDC1) in gastric cancer (GC) progression and immune cell infiltration remains unclear. This study aimed to investigate the impact of FNDC1 on GC progression and to elucidate its association with immune cell infiltration in GC. FNDC1 expression profiles in GC and paired normal tissues were analyzed using datasets from the TCGA, GTEx, and GEO databases, with validation conducted through quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). Differentially expressed genes (DEGs) associated with FNDC1 were identified through gene set enrichment analysis (GSEA) and functional enrichment analysis. We evaluated the role of FNDC1 in GC immune cell infiltration. In addition, Cox regression and Kaplan-Meier analyses were conducted on FNDC1 for its prognostic significance and correlation with clinical variables. We evaluated the role of FNDC1 in gastric cancer cell invasion and migration via Transwell and wound-healing assays following FNDC1 knockdown and overexpression. Finally, survival probabilities in GC patients were predicted by nomogram construction. FNDC1 expression in GC tissues significantly increased relative to that in matched normal samples (P < 0.001), as confirmed by qPCR and IHC (both P < 0.05). There were 359 DEGs associated with ECM Receptor Interaction, Focal Adhesion, and the Degradation of the Extracellular Matrix signaling pathway. FNDC1 expression was positively related to macrophage and NK cells infiltration (macrophage, r = 0.564, P < 0.001; NK cells, r = 0.566, P < 0.001; as validated by IHC and further confirmed by in vitro co-culture assays). Additionally, FNDC1 expression was strongly related to T stage (P < 0.001), pathological stage (P < 0.001), histological grade (P < 0.01), histological type (P < 0.001), anatomic neoplasm subdivision (P < 0.001), and unfavorable overall survival (OS, P < 0.05). In vitro cell experiments indicate that FNDC1 expression is closely associated with the invasion and migration of gastric cancer cells. Our established nomogram effectively predicted the 1-, 3-, and 5-year OS probabilities in patients with GC (C-index [95% CI] = 0.714 [0.689–0.738]). FNDC1 is strongly associated with a dismal prognostic outcome and immune cell infiltration in patients with GC.

Metabolic reprogramming of pyrimidine metabolism contributes to tumor progression; however, the oncological role of beta-ureidopropionase 1 (UPB1), the terminal enzyme in pyrimidine catabolism, remains poorly understood. This study aimed to characterize the expression profile, prognostic value, molecular alterations, immune associations, and functional significance of UPB1 across multiple cancer types, with focused validation in skin cutaneous melanoma (SKCM). UPB1 expression and its clinical relevance were evaluated using TCGA-based pan-cancer datasets and integrated bioinformatics platforms, including SangerBox, TIMER 2.0, GEPIA2, UALCAN, GSCA, cBioPortal, and LinkedOmics. Its functional effects were assessed in SK-MEL-2 and A375 melanoma cells using UPB1 overexpression, proliferation and migration assays, and Western blot analysis of epithelial–mesenchymal transition markers. UPB1 was significantly downregulated in multiple tumor types, including SKCM. Reduced UPB1 expression was associated with advanced clinicopathological features and poorer overall survival, disease-free survival, and progression-free interval in several malignancies. Genetic analyses revealed predominantly missense mutations, with the highest alteration frequency observed in SKCM, as well as tumor-specific differences in promoter methylation. UPB1 expression was positively associated with the infiltration of effector immune cells and the expression of key immunomodulatory molecules. In melanoma cells, UPB1 overexpression inhibited proliferation and migration and suppressed epithelial–mesenchymal transition, as evidenced by increased E-cadherin expression and decreased N-cadherin and vimentin expression. Collectively, these findings suggest that UPB1 functions as a tumor-suppressive factor linked to pyrimidine catabolism and may serve as a prognostic biomarker, particularly in SKCM.

Asthma remains the most prevalent chronic respiratory condition affecting pediatric populations, with no curative therapy currently available. Dendritic cells (DCs) are pivotal in initiating Th2 polarization during asthmatic responses, though molecular mechanisms governing DC activation remain incompletely elucidated. As a constituent of the membrane palmitoylated protein family, membrane-associated guanylate kinase (MAGUK) p55 subfamily member 7 (MPP7) has potential therapeutic implications for respiratory disorders, yet its specific involvement in asthma pathogenesis requires further investigation. This study aimed to elucidate MPP7’s protective effects against allergic airway inflammation by analyzing its impact on Th2 immune responses and DC functionality. Clinical data revealed notably reduced MPP7 levels in asthmatic patients’ peripheral blood samples. Experimental models using house-dust-mite (HDM)-exposed mice demonstrated that MPP7 deficiency intensified airway inflammatory responses, with pathological manifestations including amplified leukocyte infiltration, heightened Th2 cytokine production, and elevated serum levels of HDM-specific IgE. Notably, MPP7 caused a marked reduction in pulmonary CD11b+CD103− DCs populations while inhibiting DC activation via interference with NF-κB pathway signaling. These results collectively suggest that MPP7 exerts its anti-inflammatory effects through dual mechanisms involving both cellular subset modulation and intracellular signaling pathway inhibition in DCs, positioning it as a promising candidate for managing allergic respiratory disorders and associated immune-mediated conditions.

Esophageal squamous cell carcinoma (ESCC) is one of the highly lethal and aggressive malignant tumors worldwide. To effectively prevent and treat this disease, the search for novel molecular targets is of great significance for promoting the molecular diagnosis and targeted therapy of ESCC. Gene expression profiles from gene expression omnibus (GEO) datasets were normalized and analyzed to identify differentially expressed genes. Functional enrichment, protein-protein interaction network, and machine learning algorithms were applied for biomarker screening. Immune infiltration analysis and immunohistochemistry were performed to assess clinical relevance. Analysis identified 752 differentially expressed genes in ESCC, with enrichment in upregulated pathways including DNA replication and mismatch repair, and downregulated pathways such as autophagy. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses revealed complex molecular networks driving ESCC. Key hub genes and diagnostic biomarkers aurora kinase A (AURKA), kinesin family member 4 A (KIF4A), and replication factor C subunit 4 (RFC4) were identified, with high diagnostic area under the receiver operating characteristic curve values from 0.976 to 0.983. RFC4 expression correlated with mast cell infiltration patterns, showed elevated expression in ESCC tissues via immunohistochemistry, and was associated with poor prognosis. This study identifies AURKA, KIF4A, and RFC4 as potential in silico biomarkers for ESCC. This study further highlights RFC4 as a promising candidate for diagnostic and prognostic applications, offering new insights into prevention strategies for ESCC.

BACKGROUND:Toll-like receptor 7/8 agonists (TLR7/8a), such as resiquimod (R848), are highly potent in activating dendritic cells and thus hold promise for T cell-mediated tumor immunotherapies. However, the short half-life of these small molecules in the lesion and the associated systemic immunotoxicity post-leakage of the drug into the circulation make their clinical application challenging. MATERIALS:To overcome these shortcomings, we tested prolonged TLR7/8a therapy by intratumoral infusion of R848 for 25 h using a micropump to achieve durable therapeutic effects while minimizing the proinflammatory cytokine levels in the plasma post leakage of the drug into the circulation. RESULTS:The results showed that prolonged immunotherapy with R848 (as low as 1 μg) significantly suppressed tumor growth (inhibition rates up to 98%, p < 0.01) in treated mice compared to control mice receiving regular intratumoral injection of R848. Higher levels of CD86+or CD11c+ D.C.s, CD4+/CD8+/OX40+ T cells, and cytokines (TNF-α/IFN-γ) were observed in the tumors and spleens of the mice in the treated group compared to the sham group (p < 0.05), indicating efficient activation of local and abscopal immunity by prolonged therapy with R848. Furthermore, the R848 functional concentration assay demonstrated that the micropump prolonged the treatment time of R848 drugs in tumors and reduced the requirement for higher doses, enhancing safety. CONCLUSION:Taken together, this study provides new insights into TLR7/8a immunotherapy for improved clinical performance, with potential benefits for patients with superficial tumors amenable to prolonged intratumoral infusion via micropump.

Coagulation dysfunction, a common hematologic disorder with unclear pathogenesis, is influenced by environmental factors. Sodium dehydroacetate (SDA), a widely used preservative with high environmental mobility and persistence, has become an emerging organic contaminant and is increasingly recognized for its potential to disrupt immune homeostasis and induce coagulation abnormalities, yet its specific mechanisms remain poorly understood. In this study, we employed an integrated computational approach-combining network toxicology, machine learning (LASSO and XGBoost), bioinformatics, molecular docking, and molecular dynamics simulations-to systematically investigate SDA-induced coagulation dysfunction. We identified 191 potential targets, with significant enrichment in cancer-related pathways, atherosclerosis, and proteoglycans in cancer. Met proto-oncogene (Met) emerged as a core target through machine learning. Analysis of a colorectal cancer dataset (GSE52060) revealed elevated Met expression in patients with coagulation dysfunction, and receiver operating characteristic analysis indicated its strong diagnostic value (area under the curve = 0.856). Molecular docking showed stable binding between SDA and Met (-5.5 kcal/mol), further supported by molecular dynamics simulations demonstrating favorable hydrogen bonding and complex stability. This study provides a theoretical foundation for understanding SDA's role in coagulation dysfunction and supports future preventive and therapeutic strategy development.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive haematological malignancy with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. The mechanisms underlying multidrug resistance in NKTCL remain unclear and present an urgent challenge that must be addressed during clinical treatment. Multidrug-resistant NKTCL models were established using adriamycin (ADM), and cellular senescence was confirmed by markers including P16, P21, and senescence-associated β-galactosidase (SA-β-gal). Proteomic sequencing of plasma from clinical patients and resistant cells identified LCP2 as a key protein. Phosphoproteomics, mass spectrometry, and co-immunoprecipitation analyses revealed LCP2's role in mediating senescence-associated chemoresistance. An in vivo ageing microenvironment model was used to assess whether targeting the LCP2-mediated axis could eliminate chemoresistant senescent cells. Results show that ADM-resistant NKTCL cells exhibited phenotypic and senescence features. Of these, LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with senescence marker SA-β-gal. Moreover, LCP2 knockdown enhanced the chemoresistance, senescent-associated secretory phenotype secretion, and G0/G1 cell cycle arrest in NKTCL cells. Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage, telomere stress-induced senescence, and facilitating the formation of an immunosuppressive microenvironment. Importantly, targeting this axis with Epitalon and Chaetocin can partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and alleviate the immunosuppressive microenvironment to a certain extent in vivo. In conclusion, this study is the first to uncover LCP2 as a critical biomarker of senescence-related chemoresistance in NKTCL, providing a theoretical basis for the clinical translation of senolytics for treating R/R NKTCL.

Diffuse large B-cell lymphoma (DLBCL) features an immunosuppressive tumor microenvironment (TME), yet the molecular drivers connecting metabolic reprogramming to immune evasion remain poorly defined. Here, we deployed an integrative single-cell transcriptomic analysis combined with a machine learning (ML) framework to systematically identify key immune-suppressive hubs in DLBCL. Through ML-driven prioritization of a 33-gene panel, PAICS emerged as a central node within an immunosuppressive B-cell subgroup. Functional assays confirmed that PAICS promotes lymphoma proliferation, survival, and tumor growth while establishing an immunosuppressive TME-marked by reduced IFN‑γ, elevated TGF‑β and IL‑10, and enhanced CD8⁺ T cell exhaustion. Mechanistically, we uncovered the IRF4-PAICS-LDHA axis: IRF4 transcriptionally activates PAICS, which physically interacts with LDHA to augment its activity, thereby skewing the NAD⁺/NADH balance toward metabolic immunosuppression. Importantly, our AI-aided approach not only identified this axis but also predicted its vulnerability to metabolic intervention: both methotrexate treatment and LDHA knockdown restored metabolic balance, reversed T‑cell exhaustion, and suppressed tumor growth. These findings highlight the power of ML in uncovering multi-targetable metabolic-immune networks and in guiding therapeutic strategies to overcome immune evasion in DLBCL.

Background:Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (EBV+ nTNKL) has recently been delineated in the WHO-HAEM5 classification as a distinct and exceptionally rare entity. Its biology and clinical trajectory remain obscure relative to Extranodal NK/T-cell lymphoma (ENKTL). Methods:We applied spatial transcriptomics and multiplex immunofluorescence to representative ENKTL and EBV+ nTNKL specimens, integrating these data with a retrospective clinical cohort of 14 EBV+ nTNKL patients-constituting one of the largest series described to date. Results:Spatial transcriptomics revealed fundamental differences between ENKTL and EBV+ nTNKL. ENKTL, of NK-cell origin, displayed higher malignant cell density, neutrophil enrichment, and an immune-desert phenotype, whereas EBV+ nTNKL, of T-cell origin, showed reduced tumor burden, B-cell enrichment, and an immune-active microenvironment with abundant cytotoxic T cells and PD-1/PD-L1 expression. Intercellular communication analyses further highlighted distinct signaling programs-TGF-β/BMP-driven tumor-neutrophil interactions in ENKTL versus CXCL/CCL-GPCR-mediated macrophage crosstalk in EBV+ nTNKL. In a retrospective cohort of 14 EBV+ nTNKL patients, the disease was frequently complicated by hemophagocytic lymphohistiocytosis and conferred significantly inferior survival, although selected patients achieved durable responses with immune checkpoint inhibitors or CAR-T therapy. Conclusion:This study delineates the immunologic and molecular architectures of ENKTL and EBV+ nTNKL, providing rare insights into this understudied lymphoma. Despite limited sampling, these findings underscore the central role of EBV latency programs and tissue context in shaping tumor ecology and suggest avenues for subtype-tailored therapeutic strategies.

Pulmonary infections remain a leading cause of morbidity and mortality worldwide. However, conventional microbiological tests (CMTs) frequently fail to identify the causative pathogens, owing to their limited sensitivity, prolonged turnaround times, and inherent inability to detect fastidious or emerging organisms. In this context, targeted next-generation sequencing (tNGS) has emerged as a promising molecular approach, enabling rapid, sensitive, and comprehensive detection of respiratory pathogens directly from clinical specimens. This study evaluated the clinical application of tNGS in the etiological diagnosis of pulmonary infections. This study aimed to systematically characterize the pathogen spectrum, antimicrobial resistance (AMR) gene distribution, and infection-related immune cytokine dynamics in these patients. A retrospective analysis was conducted on patients with pulmonary infections who underwent bronchoalveolar lavage fluid (BALF) testing using tNGS between August 2023 and July 2024. We performed a clinical evaluation of tNGS findings and compared its diagnostic performance with that of CMTs for pathogen identification. The analysis of tNGS results from 733 clinical specimens revealed a pathogen detection positivity rate of 95.63

BackgroundThyroid lymphoma (TL) is a rare malignancy. Its diagnosis is challenging due to non-specific clinical features, with management controversies, concurrent with Hashimoto’s thyroiditis (HT), and heterogeneous prognoses across subtypes. This study aimed to analyze clinical spectrum and explore optimal treatment strategies to improve prognosis of TL.MethodsA retrospective cohort study was conducted on 61 patients with TL diagnosed in the First Affiliated Hospital of Zhengzhou University from 2014 to 2025.ResultsAmong 61 patients, 67.2% had concurrent HT. The TL+ group (TL with extrathyroid involvement, 11 patients, 18.0%) showed more frequent subdiaphragmatic lymph node involvement (p<0.001) and perivascular lymph node involvement (p=0.003) compared with the iTL group (isolated TL, 50 patients, 82.0%). With a median follow-up of 22 months, the 1-, 3-, and 5-year OS rates were 85.0%, 78.4%, and 75.6%, and PFS rates were 76.5%, 71.7%, and 63.1%. DLBCL was the most common histological subtype, accounting for 60.7% of all TL cases. In patients with thyroid diffuse large B-cell lymphoma (TDLBCL), age ≥60 years and C-myc expression ≥50% were independent risk factors for shorter PFS, whereas chemotherapy was independently associated with improved PFS and OS. Surgery alone without chemotherapy was associated with shorter PFS in univariate analysis.ConclusionsTL with extrathyroidal involvement shares features with isolated disease but requires Ann Arbor staging-guided management. Chemotherapy was independently associated with improved PFS and OS in patients with thyroid diffuse large B-cell lymphoma, whereas older age and high C-myc expression were independently associated with inferior PFS.

Oxidized low-density lipoprotein receptor 1 (OLR1) in gastric cancer (GC) progression and immune cell infiltration remains unclear. This study aimed to investigate the impact of OLR1 on GC progression and to elucidate its association with immune cell infiltration in GC. OLR1 expression profiles in GC and paired normal tissues were analyzed using datasets from the TCGA, GTEx, and GEO databases, with validation conducted through quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). Differentially expressed genes (DEGs) associated with OLR1 were identified through gene set enrichment analysis (GSEA) and functional enrichment analysis. We evaluated the role of OLR1 in GC immune cell infiltration. In addition, Cox regression and Kaplan-Meier analyses were conducted on OLR1 for its prognostic significance and correlation with clinical variables. We evaluated the role of OLR1 in gastric cancer cell invasion and migration via Transwell and wound-healing assays following OLR1 knockdown and overexpression. Finally, survival probabilities in GC patients were predicted by nomogram construction. OLR1 expression in GC tissues significantly increased relative to that in matched normal samples (P < 0.001), as confirmed by qPCR and IHC (both P < 0.05). There were 268 DEGs associated with Staphylococcus aureus infection, protein digestion and absorption signaling, and the estrogen signaling pathway. OLR1 expression was positively related to macrophage infiltration (r = 0.742, P < 0.001, as validated by IHC). Additionally, OLR1 expression was strongly related to histological grade (P < 0.001), histological type (P < 0.05), T stage (P < 0.01), pathological stage (P < 0.05), and unfavorable overall survival (OS, P < 0.05). In vitro findings indicate that OLR1 enhances the invasive and migratory abilities of gastric cancer cells. Our established nomogram effectively predicted the 1-, 3-, and 5-year OS probabilities in patients with GC (C-index [95% CI] = 0.649 [0.624-0.675]). OLR1 is strongly associated with a dismal prognostic outcome and immune cell infiltration in patients with GC.

Lung cancer frequently metastasizes to the brain, posing significant therapeutic challenges. To address this, we developed HLP@SiTGF-β1, a hybrid biomimetic nanoparticle integrating phototherapy, gene silencing, and immunotherapy. The system comprises a ZIF-8 core loaded with TGF-β1-targeting siRNA (SiTGF-β1), enveloped by a hybrid membrane fusing liposomes (loading the phototherapeutic agent IR-780) with Lewis lung carcinoma (LLC) cell membranes. This design enables homologous tumor targeting, prolonged circulation, and immune evasion. In vitro and in vivo studies demonstrated that near-infrared (NIR) irradiation triggers immunogenic cell death (ICD) via photodynamic (PDT) and photothermal (PTT) effects, while siRNA-mediated TGF-β1 knockdown alleviates tumor hypoxia, enhances PDT efficacy, reduces regulatory T cell (Treg) differentiation, and promotes cytotoxic CD8+T cell infiltration. The nanoparticles efficiently penetrated the blood–brain barrier in a brain metastasis model, significantly suppressing intracranial tumor growth under NIR light. This “four-in-one” strategy—combining PDT, PTT, gene therapy, and immunotherapy—offers a promising multimodal platform for treating lung cancer and its brain metastases.

Bidens pilosa L (BL), known for its anti-inflammatory, antioxidant, and anticancer properties across multiple malignancies, was investigated for its potential therapeutic effects against esophageal squamous cell carcinoma (ESCC). Through integrative network pharmacology and computational approaches, 10 bioactive compounds from BL were identified from HERB 2.0, symMap, BATMAN-TCM (target prediction score cutoff = 20, adjusted P-value = 0.05 for target analyses), TCMSP (oral bioavailability ≥ 30

Tumor therapy has historically been a global research focus, with phototherapy garnered significant attention as a innovative treatment modality. However, the antioxidant defense system in the tumor microenvironment, characterized by excessive glutathione (GSH) and thiol-containing proteins, often limits the effectiveness of photodynamic therapy. In this study, we report the development of a new multifunctional integrated nanozyme with thioredoxin reductase-oxidase (TrxRox) and GSH-oxidase (GSHox)-like activities. This nanozyme, termed AuI-incorporated MOFs, was synthesized by embedding monovalent Au nanozymes into a light-sensitive metal-organic framework (MOFs) structure using an in-situ oxidation-reduction method. The intergrated AuI nanozyme exhibited inhibitory effects on TrxR and presented significant anti-tumor properties. Moreover, the integrated nanozyme also demonstrates peroxidase-like activity, catalyzing the decomposition of hydrogen peroxide (H2O2) into hydroxyl radicals (center dot OH). Additionally, this nanomedicine effectively depletes existing GSH and TrxR, thereby enhancing the efficacy of photodynamic and photothermal therapy. Notably, under light conditions, this nanozyme induces oxidative stress within cells, leading to apoptosis and necrosis of tumor cells. Of note, it triggers immunogenic cell death and activating antigen-presenting cells to convert cold tumors into hot tumors. Therefore, AuI-incorporated MOFs nanozyme demonstrates promising potential in photo- immunotherapy, offering new insights and strategies for tumor therapy.

Context: Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with a high propensity for drug resistance, particularly to anthracyclines like adriamycin (ADM). The molecular mechanisms of ADM resistance in NKTCL are not fully understood. Objective: In this study, we aimed to elucidate the role of YTHDF2 in the regulation of SLC16A9 mRNA stability and its implications in ADM resistance in NKTCL. Materials & methods: The study examined the expression changes of SLC16A9 under varying concentrations of ADM and manipulated the expression levels of SLC16A9 and YTHDF2 through overexpression and knockdown. By analyzing the levels of m6A modification, it was revealed that YTHDF2 regulates SLC16A9 expression via the m6A pathway, thereby influencing ADM resistance. This conclusion was further validated by in vivo experiments. Results: Our results showed that overexpression of SLC16A9 enhanced ADM resistance, while knockdown of SLC16A9 increased sensitivity to ADM. Further investigation revealed that ADM treatment reduces m6A modification levels on SLC16A9 mRNA, which is associated with decreased binding of YTHDF2 to SLC16A9 mRNA, leading to increased SLC16A9 expression. We also found that overexpression of YTHDF2 reduced SLC16A9 expression and increased ADM sensitivity, whereas knockdown of YTHDF2 had the opposite effect. In vivo experiments using a nude mouse model further confirmed that SLC16A9 knockdown reduces tumor growth and enhances sensitivity to ADM. Conclusions: our study provides direct evidence that YTHDF2 modulates ADM resistance in NKTCL by regulating the m6A modification of SLC16A9. Targeting the YTHDF2-m6A-SLC16A9 axis may offer a novel therapeutic strategy to overcome chemotherapy resistance in NKTCL.

Reactive oxygen species (ROS) have been widely studied for cancer therapy. Nevertheless, instability and aspecific damages to cellular biomolecules limit the application effect. Recently, significant research efforts have been witnessed in the flourishing area of metal nanoclusters (NCs) with atomically precise structures for targeted release of ROS but few achieved success towards targeting tumor microenvironment. In this work, we reported an atomically precise nanocluster Cu6(C4H3N2S)6 (Cu6NC), which could slowly break and generate ROS once encountered with acidic. The as-prepared Cu6NC demonstrated high biological safety and efficient chemodynamic anti-tumor properties. Moreover, Cu6NC enabled transient release of ROS and contained targeting behavior led by the tumor microenvironment. Both in vitro and in vivo experiments confirmed that Cu6NC demonstrated a low cytotoxicity for normal cells, while presented high cytotoxicity for tumor cells with a concentration-dependent manner. This work not only reported a promising candidate for chemodynamic cancer therapy, but also paved the route to address clinical issues at the atomic level.