INTRODUCTION:Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent cardiotoxicity. Currently, there are no effective strategies to prevent or reverse DOX-mediated myocardial injury, highlighting the urgent need for novel therapeutic approaches. OBJECTIVES:In this study, the cardioprotective effects of crocin, a natural compound derived from Crocus sativus, were investigated in the context of DOX-mediated cardiotoxicity. METHODS:Cardiac function, mitochondrial morphology, ROS production, and ATP content were evaluated in both in vitro and in vivo models of DOX-mediated cardiotoxicity. RNA sequencing was performed to identify key regulatory pathways affected by crocin. Mitophagy-related mechanisms were investigated through molecular and cellular assays, including immunofluorescence and Western blot analysis of PTEN-induced kinase 1 (PINK1)-associated signaling. PINK1 knockdown and mitophagy inhibition were performed to assess the impact on the cardioprotective effects of crocin. RESULTS:Crocin treatment preserved cardiac function and mitigated DOX-mediated myocardial injury in both in vitro and in vivo models, as evidenced by restored left ventricular ejection fraction, reduced mitochondrial ROS accumulation, restoration of ATP production, and improved mitochondrial morphology. Transcriptomic analysis revealed that crocin upregulated PINK1 expression, a key initiator of mitophagy. Functional assays further confirmed that crocin restored mitophagy activity suppressed by DOX exposure. The cardioprotective effects of crocin were abolished upon PINK1 knockdown or mitophagy inhibitor, highlighting the essential role of PINK1-dependent mitophagy in mediating crocin's effects. CONCLUSIONS:Crocin protects against doxorubicin-induced cardiotoxicity by activating PINK1-mediated mitophagy and maintaining mitochondrial homeostasis. These findings highlight crocin as a potential therapeutic agent for mitigating DOX-mediated cardiotoxicity.

Immune checkpoint blockade (ICB) has significantly advanced tumor therapy, yet its overall response rates remain limited and are often accompanied by immune-related adverse effects. Immunogenic cell death (ICD), a specialized form of regulated cell death, elicits antitumor immunity through the release of damage-associated molecular patterns and cytokines. This review systematically examines the mechanisms by which ICD enhances the efficacy of ICB therapy and evaluates its potential for clinical translation. ICD facilitates the recruitment of dendritic cells into the tumor microenvironment via “find me” signals and, through the exposure of “eat me” signals, enables dendritic cell-mediated phagocytosis and antigen presentation of tumor cells. This cascade effectively transforms immunologically “cold” tumors into “hot” tumors, augmenting cytotoxic T lymphocyte infiltration and function, thereby improving ICB therapeutic outcomes. Additionally, ICD promotes the formation of tertiary lymphoid structures, which further remodel the tumor microenvironment and support sustained immune surveillance. Although preclinical studies underscore the synergistic potential of combining ICD inducers with ICB, clinical trial outcomes have been variable, with efficacy influenced by tumor heterogeneity, treatment sequencing, and the immunosuppressive tumor microenvironment. Future investigations should focus on optimizing ICD induction protocols, developing specific biomarkers, and designing personalized combination strategies to enable more precise and effective immunotherapeutic interventions in oncology.

Epstein-Barr virus (EBV)-positive neuroendocrine carcinoma (NEC) of the nasopharynx is a rare malignancy with poor prognosis and lacks squamous markers, rendering it biologically distinct from nasopharyngeal carcinoma (NPC) of squamous epithelial origin. However, its molecular features remain largely undefined, and the entity has not been formally recognized as a nasopharyngeal carcinoma subtype, substantially limiting advances in its diagnosis and treatment. In this study, we performed whole-exome sequencing on seven EBV-positive nasopharyngeal NECs. These tumors exhibited a high tumor mutational burden and recurrent mutations in TP53, APC, and PROK2, with enrichment of alterations in the TP53/WNT, NOTCH, and RTK/RAS/PI3K pathways-mimicking the genomic landscape of NECs at other anatomical sites but clearly diverging from that of NPC. In addition, we identified potentially actionable alterations involving TP53 and KMT2A, suggesting avenues for targeted therapeutic exploration. Collectively, our findings provide molecular evidence supporting EBV-positive NEC of the nasopharynx as a distinct clinicopathologic entity, and offer valuable insights into its oncogenesis and potential therapeutic vulnerabilities.

Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl4-induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone.

AIM:Many patients with non-small cell lung cancer (NSCLC) do not derive clinical benefit from immune checkpoint inhibitors (ICIs), and a reliable method for identifying potential responders is lacking. This study aims to establish an optimized patient-derived organoids (PDOs) culture system and develop a novel organoid-peripheral blood mononuclear cell (PBMC) co-culture platform to evaluate response to ICIs. METHODS:We optimized culture conditions for patient-derived NSCLC organoids by integrating conditional reprogramming techniques. ICIs response was assessed with an organoid-PBMC co-culture system. The accuracy of this ex vivo system was validated by comparing its results with efficacy of ICI therapy in both an in vivo humanized mouse xenograft model and the corresponding patient's clinical response. Moreover, the genomic stability of the organoids during serial passaging was monitored through gene sequencing. RESULTS:An optimal indirect co-culture system was established, culturing organoids with 25% Matrigel. This system consisted of 40 Gy-irradiated Swiss 3T3-J2 fibroblasts in an upper chamber and primary NSCLC cells in a lower chamber, using F-medium (DMEM/F-12 (3:1, v/v) + 10 µM Y-27632) supplemented with 0.5 µM A83-01. This method achieved an 85.59% (95/111) success rate. Using this platform, we evaluated PD-1 antibody efficacy with the organoid-PBMC co-culture system in 70 cases. For in vivo validation, a direct patient-derived organoid xenograft (PDOX) models were established in humanized mice reconstituted with the corresponding patient's PBMCs. Notably, the ex vivo results demonstrated a strong correlation with both the in vivo validation data and patients' actual clinical responses to ICIs, yielding a sensitivity of 100% and a specificity of 62.20%. CONCLUSION:We developed a novel, simple, rapid and reliable organoid-PBMC co-culture system for screening the response of NSCLC patients to ICI therapy.

Currently, relying on a single biomarker to predict the prognosis of melanoma patients is inefficient, particularly in the context of immunotherapy. We aimed to characterize tumor microenvironment (TME) subtypes and develop a robust risk classification model for melanoma prognostication. In this study, we performed unsupervised clustering on multiple melanoma datasets and identified three distinct TME subtypes based on the expression patterns of 51 gene signatures. Furthermore, we constructed a risk model using public melanoma cohorts as the training set and validated it via multiplex immunohistochemical staining in our own tumor samples. Three unique TME subtypes (designated TME-A, -B, and -C) were identified, and these were significantly associated with overall survival, disease-specific survival and distant metastasis-free survival. Using weighted gene co-expression network analysis and the least absolute shrinkage and selection operator regression model, we further identified three pivotal genes: CXCR6, CD45, and PD-1. Based on these three genes, we developed a risk stratification model named the microenvironment subtype-related gene risk score (MSGRS), which effectively predicted the prognosis of melanoma patients across multiple independent cohorts, including populations treated with immunotherapy. Importantly, high CXCR6 expression was associated with favorable clinical outcomes, increased immune cell infiltration, and distinct spatial organization of CD8 + and CD69 + immune cells within the TME. Our findings demonstrate that TME characteristics, including immune cell density and spatial distribution, and particularly the CXCR6-derived risk model, serve as robust predictors of patient survival, even in the setting of immune checkpoint inhibitor therapy.

ABSTRACT Objective Hereditary cancer risk assessment has predominantly focused on HER2‐negative breast cancer (BC), with limited characterization of germline pathogenic variants (GPVs) in HER2‐positive disease. This study aimed to delineate the prevalence, clinicopathological correlates, and clinical implications of GPVs in a cohort of HER2‐positive BC patients. Methods We retrospectively reviewed BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center from 2014 to 2024. GPV profiles, clinicopathological features, and survival outcomes were compared between HER2‐positive and HER2‐negative patients, with additional stratified analysis in HER2‐positive GPV carriers. Results Among 1692 BC patients, 1,499 patients met NCCN high‐risk criteria. In multigene panel testing, GPVs were identified in 18.1% (52/288) of HER2‐positive BC and 22.4% (269/1,201) of HER2‐negative BC patients. HER2‐positive GPV carriers exhibited distinct molecular profiles, with higher frequencies of BRCA2 (23/52, 44.2%) and TP53 (14/52, 26.9%) mutations and a lower BRCA1 prevalence (6/52, 11.5%) compared to HER2‐negative carriers (BRCA2: 106/269, 37.9%; TP53: 9/269, 3.3%; BRCA1: 117/269, 43.5%). Clinically, HER2‐positive carriers were diagnosed at a younger median age, had higher hormone receptor (HR) positivity, and less frequently reported a family history of BRCA‐related cancers. GPVs were not associated with increased locoregional recurrence or distant metastasis in HER2‐positive BC but significantly elevated the risk of contralateral BC and other secondary primary cancers—a risk particularly pronounced in TP53 carriers. Conclusions HER2‐positive BC patients harbored a distinct GPV spectrum compared to HER2‐negative patients. While GPVs did not worsen primary BC‐specific outcomes, they conferred a significantly increased risk of second primary cancers, underscoring the clinical utility of multigene panel testing for comprehensive risk stratification and long‐term management in this population. Study Limitations This retrospective, single‐center study comprised a clinically enriched high‐risk cohort, which may limit the generalizability of prevalence estimates. The extended inclusion period and evolving classification standards, despite reannotation, represent inherent methodological constraints.

Purpose:The necessity of tight glycemic management in non-small cell lung cancer (NSCLC) remains controversial. This study aimed to determine whether baseline fasting plasma glucose (FPG) levels could serve as an independent prognostic marker for survival outcomes in advanced NSCLC. Patients and methods:This study included 960 patients with advanced NSCLC, who were categorized into low (< 3.9 mmol/L), normal (3.9-6.1 mmol/L), and high FPG groups (> 6.1 mmol/L) based on pre-treatment FPG levels. The analyzed covariates included demographics, clinical characteristics, oncogenic mutation status, and first-line treatments. Survival curves with log-rank tests were estimated to compare survival differences between groups. Univariate and multivariate Cox proportional hazards regression were performed to investigate the prognostic factors. Furthermore, smooth curve fitting and piecewise Cox regression were used to explore the non-linear relationships between FPG and mortality risk, while subgroup analyses were employed to test interactions. Results:Both low (12.0 vs. 18.5 months, P = 0.0093) and high (14.4 vs. 18.5 months, P = 0.0049) FPG levels were significantly associated with shorter median survival times compared to normal FPG levels. Multivariable analyses further identified low FPG (HR 1.41, 95% CI 1.06-1.88; P = 0.0196) and high FPG (HR 1.43, 95% CI 1.11-1.85; P = 0.0059) as independent prognostic risk factors. Smooth curve fitting and piecewise Cox proportional hazards models revealed a negative linear relationship between FPG levels and mortality risk (HR 0.70, 95% CI 0.52-0.94; P = 0.0185) when FPG was below the breakpoint of 4.46 mmol/L, and a positive linear relationship (HR 1.11, 95% CI 1.04-1.19; P = 0.0015) when FPG exceeded the breakpoint. Subgroup analyses consistently supported these findings across all patient subgroups, with no specific population exhibiting distinct outcomes. Conclusion:Abnormal FPG levels are independent risk factors for the long-term prognosis of advanced NSCLC. Further prospective multicenter studies are needed to confirm these associations and clarify whether glycemic assessment and management influence survival outcomes.

The global rise of non-communicable diseases (NCDs) presents an urgent public health challenge, particularly in regions undergoing rapid economic and demographic transitions. Guangdong Province, China’s most populous and economically advanced region, is experiencing a substantial and accelerating burden of NCDs. However, large-scale, population-based cohorts from this region remain scarce, limiting insights into region-specific disease determinants and prevention strategies. The Guangdong Biobank Cohort (GDBC) was established in 2017, enrolling 35,081 participants aged 40–84 years from urban and rural areas of Zhongshan City in the Pearl River Delta. At baseline, comprehensive data on 346 variables—including lifestyle, environmental exposures, medical histories, physical examinations, and laboratory profiles—were collected via a cloud-based member management information system (MMIS), alongside blood and saliva samples for biobanking. A sub-cohort underwent genome-wide genotyping (N = 2,530) and oral microbiome profiling via 16 S rRNA sequencing (N = 2,049). During dynamic follow-up, 44.2

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with ectopic fat accumulation and alterations in adipose tissue function. However, the relationships of structural and thermogenic adipose imaging markers with hepatic steatosis remain incompletely understood. This study aimed to jointly evaluate the cross-sectional associations of epicardial adipose tissue (EAT) thickness and infrared thermography (IRT)-derived brown adipose tissue (BAT)-related thermogenic activity with controlled attenuation parameter (CAP)-defined hepatic steatosis severity in adults with suspected MASLD. Methods: In this cross-sectional study, 207 adults undergoing clinical evaluation for suspected MASLD underwent transient elastography to obtain the controlled attenuation parameter (CAP) for hepatic steatosis assessment. EAT thickness was measured by transthoracic echocardiography, and BAT-related thermogenic activity was assessed by infrared thermography using the supraclavicular-to-chest temperature difference (ΔTemp). Associations of these adipose imaging phenotypes with CAP were evaluated using correlation analyses, sequential multivariable linear regression models, and BAT-stratified analyses. Results: EAT thickness increased progressively across CAP-defined steatosis grades (p < 0.001) and was positively correlated with CAP (r = 0.637, p < 0.001), whereas ΔTemp decreased with increasing steatosis severity and was inversely correlated with CAP (ρ = −0.277, p < 0.001). In sequential multivariable regression models, EAT thickness remained independently associated with CAP across adjustments for age, sex, body mass index, metabolic variables, and ΔTemp (standardized β = 0.559–0.623; all p < 0.001). Both EAT thickness and ΔTemp were independently associated with CAP in the fully adjusted model, with a stronger association for EAT thickness (standardized β = 0.559 vs. −0.167; p < 0.001 and p = 0.004, respectively). Stratified analyses demonstrated consistent associations between EAT thickness and CAP across both BAT-low and BAT-high activity groups. Conclusions: Greater EAT thickness and lower IRT-derived ΔTemp were independently associated with greater CAP-defined hepatic steatosis severity, with EAT thickness showing the stronger standardized association. These complementary structural and thermogenic imaging correlates warrant prospective evaluation to clarify their directionality and clinical relevance.

This study aimed to explore whether alpha-fetoprotein (AFP) promotes resistance of hepatocellular carcinoma (HCC) cells to lenvatinib by regulating the activity of lactate dehydrogenase A (LDHA) and triggering the Warburg effect. Analysis of 30 clinical HCC samples revealed that the expression of AFP and LDHA in cancer tissues was significantly higher than that in adjacent tissues and that there was a positive correlation between their expression levels. Cell function experiments (such as MTT and colony formation assays) confirmed that AFP significantly enhances the resistance of HCC cells to lenvatinib. Mechanistic studies have found that AFP can promote glycolysis in HCC cells (manifested as an enhanced Warburg effect, increased glucose consumption, lactate production, and ATP production) and upregulate the expression of glycolysis-related proteins, which is dependent on LDHA. Further mechanistic studies indicated that AFP regulates LDHA activity by activating the PI3K/AKT signaling pathway. Therefore, this study revealed that AFP enhances glycolysis by stimulating the activation of the PI3K/AKT/LDHA signaling axis, thereby inducing resistance of HCC cells to lenvatinib. This study provided a new theoretical basis for overcoming lenvatinib resistance by targeting AFP and inhibiting LDHA expression.

Objectives:Several clinical trials have demonstrated promising outcomes with thoracic radiotherapy (TRT) in patients with advanced lung adenocarcinoma (LUAD). However, a subset of patients derives no significant survival benefit from TRT. This study aimed to develop a risk model integrating biomarkers and clinical factors to identify patients most likely to benefit from TRT. Methods:Prognostic proteins associated with LUAD survival were identified using data from The Cancer Proteome Atlas. Immunohistochemical analysis was performed to evaluate protein expression in patients with advanced LUAD treated at our institution between 2015 and 2019. Univariate and multivariate Cox regression analyses were conducted to determine clinical factors influencing prognosis. A risk model combining biomarkers and clinical variables was constructed to generate individualized risk scores. Results:Four proteins, PAI-1, KU80, FOXO3A_pS318S321, and CKIT, were selected for further analysis. A total of 272 patients were divided into training (n = 181) and validation (n = 91) cohorts. Six prognostic factors including N-stage, presence of sensitive mutations, brain metastasis, adrenal metastasis, leukocyte count, and expression levels of PAI-1 and KU80 were incorporated into the risk model. Patients were stratified into low- and high-risk groups based on calculated risk scores. TRT significantly improved median survival time (69.0 vs. 39.3 months, p = 0.003) and overall survival (67.4 vs. 33.0 months, p = 0.035) in low-risk patients, but not in high-risk patients (median survival time: 19.8 vs. 18.2 months, p = 0.186; overall survival: 19.4 vs. 19.9 months, p = 0.607) for two cohorts. Conclusion:Multiple biomarkers and clinical variables are associated with prognosis in LUAD. The risk model developed herein indicates that TRT confers a survival benefit exclusively in patients classified as low risk.

CCCTC-binding factor (CTCF) is a highly conserved DNA-binding protein crucial for 3D genome organization and gene regulation. Previous studies have shown that CTCF overexpression in hepatocellular carcinoma (HCC) is associated with poor prognosis. This study aimed to elucidate the molecular mechanisms underlying CTCF's role in HCC pathogenesis and identify the downstream effectors that mediate its oncogenic functions. We generated CTCF knockout HCC cell lines (Huh7 and PLC5) using the CRISPR-Cas9 technology. CTCF knockout significantly reduced HCC cell proliferation, colony formation, migration, and invasion capabilities while inducing cellular senescence. Chromatin immunoprecipitation-sequencing analysis revealed that CTCF knockout in HCC cells preferentially affected its binding to promoters and enhancers rather than topologically associating domain boundaries. In contrast, genes that were commonly downregulated in the two CTCF knockout cell lines were significantly enriched in the energy metabolism pathway, and fatty acid desaturase 1 (FADS1) emerging as a key CTCF target gene. We further found that CTCF and FADS1 expression levels are highly correlated in clinical HCCs with high expression levels associated with poor patient survival. FADS1 knockdown recapitulated the CTCF knockout phenotypes, including reduced ATP levels, impaired glycolysis and oxidative phosphorylation, and decreased NAD+/NADH ratios. Re-expression of FADS1 in CTCF knockout cells significantly upregulated ATP level associated with enhanced glycolytic and respiratory capacity. In vivo xenograft studies confirmed that tumor growth was significantly inhibited by CTCF or FADS1 depletion. This study highlighted a CTCF-FADS1 axis that predominately regulates energy metabolism in HCC cells with profound prognostic and therapeutic implications for HCCs.

While cisplatin-based chemoradiotherapy regimens (gemcitabine-cisplatin [GP] and docetaxel-cisplatin-5-fluorouracil [TPF]) remain standard treatments for advanced nasopharyngeal carcinoma (NPC), 30-40% of patients exhibit intrinsic chemoresistance, resulting in therapeutic failure. The molecular underpinnings of this resistance are poorly characterized. Through integrative multi-omics profiling, we identified Mitochondrial Ribosomal Protein S7 (MRPS7) and Mitochondrial Ribosomal Protein S23 (MRPS23) as novel drivers of cisplatin resistance in NPC. Mechanistically, integrated single-cell RNA-seq (scRNA-seq) analysis, mass spectrometry, and functional studies revealed that MRPS7 and MRPS23 stabilized β-catenin by inhibiting its ubiquitination, thereby promoting β-catenin-mediated cancer stemness and epithelial-mesenchymal transition (EMT) to establish cisplatin resistance in NPC. Additionally, we identified Ubiquitin Specific Peptidase 10 (USP10) as a critical upstream regulator that protects MRPS7/23 from proteasomal degradation and sustaining their oncogenic activity. Notably, Spautin-1, a potent USP10 inhibitor, demonstrates synergistic therapeutic activity with cisplatin in diminished tumor growth and metastasis in NPC mice. This research established the USP10-MRPS7/MRPS23-β-catenin axis as a promising precision medicine strategy to combat metastatic dissemination and reverse cisplatin chemoresistance in advanced NPC, which offers a promising opportunity to develop cisplatin sensitizers for the clinical translation of NPC therapies.

Background: Annually, more than 550,000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) using invasive techniques, emphasizing the need for non-invasive diagnostic methods. Thus, our investigation aimed to create radiomics models that could forecast patients' MMP13 expression levels. Methods: This study was based on downloading genomic data and enhanced computed tomography (CT) images of HNSCC patients from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA) databases for prognostic analyses, image feature extraction, and construction of the radiomics models. Survival analysis (Kaplan-Meier survival curve, COX regression analysis, subgroup analysis, and interaction test) was used to explore the prognostic value of MMP13 in HNSCC. Correlation analysis, differential analysis of immune cell infiltration and enrichment analysis were used to explore the potential molecular mechanisms of CXCL8 expression and its relationship with the immune microenvironment. Radiomics models were constructed and Rad-score-based prediction of MMP13 and epithelial-mesenchymal transition (EMT) expression in HNSCC tissues was performed. Finally, intraclass correlation coefficient (ICC) was used to evaluate the consistency of radiomics features. Results: TCGA had a total of 483 HNSCC patients, of which high (n=326) and low (n=157) MMP13-expressing groups were used in the survival analysis. The MMP13 high-expression and low-expression groups had respective median survival times of 36.43 and 65.73 months. Tumors expressed MMP13 at a substantially greater level than normal tissue. We established the Gradient Boosting Machine (GBM) model and the logistic regression (LR) model, respectively. The area under the curve (AUC) value in the training set was 0.864 (GBM) and 0.746 (LR), and in the validation set was 0.79 (GBM) and 0.73 (LR). The Hosmer-Lemeshow goodness-of-fit test and calibration curve both showed consistency (P>0.05) between the true and predicted values in GBM model. The decision curve analysis (DCA) display model exhibited good clinical practicality in both models. Conclusions: A noteworthy association was observed between MMP13 expression and the prediction of HNSCC. Predicting MMP13 expression levels may be accomplished with the use of radiomics, which is based on contrast-enhanced computed tomography (CECT).

Papillary thyroid cancer is one of the most common malignancies in pediatrics, with increasing prevalence. We analyzed the single-cell transcriptomic landscape from 11 pediatric patients. The compositions and functions in the tumor microenvironment showed remarkable differences. Endo_tip was primarily from tumor, receiving angiogenesis-associated signals from epithelia. Abundant immune cells infiltrated into tumor. SPP1+ M2-macrophage and tumor cells interacted with T cells via immunosuppressive ligand-receptor pairs. Trajectory inference identified genes in evolutionary branchpoints that may participate in tumor progression. Analyzing the correlation of genes with thyroid differentiation score, clinicopathological features, and prognosis, we identified that FXYD5 might play a key role. RNA-seq data showed FXYD5 mediated proliferation and migration via apoptosis and adhesion processes. Compared with adults, epithelia in pediatrics exhibit higher enrichment in tumor-associated pathways; however, the differences in tumor microenvironment are less pronounced. Our findings reveal a heterogeneous microenvironment of pediatric PTC and identify FXYD5 as a potential prognostic and therapeutic marker.

Glioma is a highly aggressive brain tumor with a poor prognosis. Photodynamic therapy (PDT) induces antitumor immunity, a key mechanism of its efficacy. Dendritic cell-derived exosomes (Dexs) are crucial for tumor antigen presentation and T-cell activation. Dexs represent a promising cell-free strategy for cancer immunotherapy. Understanding the role of Dexs in PDT-induced immunity may enhance PDT efficacy. GL261 glioma cells were subjected to PDT, followed by co-culture with dendritic cells (DC) to obtain PDT-Dexs. Flow cytometry and ELISA were used to assess the effects of PDT-Dexs on DC maturation and T-cell activation. MicroRNA sequencing was performed on PDT-Dexs. The effect of PDT-Dexs on tumor growth and survival was evaluated in immune-competent and immune-deficient glioma model mice. Co-incubation with PDT-Dexs significantly increased DC maturation and T-cell activation. Sequencing revealed 156 up-regulated microRNAs, miR-152-3p was validated as a key functional miRNA that promotes DC maturation by targeting DNMT1 to upregulate MyD88 expression. PDT-Dexs entered the systemic circulation, increasing the serum IL-2, IFN-γ, and TNF-α levels. In immunocompetent mice, PDT-Dexs increased CD3 + CD4+ and CD3 + CD8+ T-cell percentages, slowed tumor growth, prolonged survival, and were associated with enhanced CD8 + T-cell infiltration and tumor cell apoptosis. Crucially, PDT-Dexs failed to inhibit tumor growth or improve survival in immunodeficient nude mice. PDT-Dexs promote DC maturation and T-cell activation, improving antitumor immunity and PDT efficacy. Combining of PDT with PDT-Dexs further improves antitumor immunity and PDT efficacy. PDT-Dexs warrants further investigation as a potential strategy for enhancing antitumor immunity in glioma.

Background:Efferocytosis plays a critical role in clearing apoptotic tumor cells and suppressing inflammation in hepatocellular carcinoma (HCC). This study aimed to identify efferocytosis-related genes (ERGs) with prognostic value and develop a predictive model for HCC outcomes. Methods:Using public HCC transcriptomic and clinical data, we identified 13 differentially expressed ERGs (DE-ERGs) from 3,866 DEGs and 74 known ERGs. Cox regression analysis selected SLC26A6, TYRO3, and PDK4 as key prognostic genes for risk model construction. The model, combined with pathologic T stage in a nomogram, showed high predictive accuracy for patient survival. Results:Totally 13 DE-ERGs were gained by overlapping 3,866 DEGs and 74 ERGs, and SLC26A6, TYRO3, and PDK4 were identified as prognosis genes for constructing a risk model with highly proficient in assessing the risk of HCC patients. Then, both risk score and pathologic T stage were recognized as independent factors prognosticating the outcome of HCC patients. Afterwards, we constructed a nomogram utilizing risk score and pathologic T stage to achieve high accuracy in predicting the survival outcomes of HCC patients. Groups at low risk demonstrated enrichment in pathways related to biometabolism and immune response, such as "fatty acid metabolism" and "complement and coagulation cascades". Additionally, the strongest positive and negative correlation were observed from activated CD4+T cell and TYRO3 (cor = 0.37), as well as natural killer cell and SLC26A6 (cor = -0.35), respectively. And risk score exhibited strong predictive capacity in response to immunotherapy. Moreover, lncRNA-miRNA-mRNA network included complex interaction pairs, such as TYRO3-hsa-miR-203b-5p-NUTM2A-AS1. There were 61 drugs with significant differences in IC50 between the high and low risk groups, such as BI.2536 and PD-173074. Single-cell analysis identified hepatocytes as the key cell population, exhibiting dynamic prognostic gene expression during differentiation and disease-specific alterations in cell-cell communication through ligand-receptor interactions. Conclusion:We identified three prognostic genes associated with efferocytosis in HCC and integrated them into a risk prognostic model. These genes not only serve as signatures for predicting HCC prognosis but also offer insights into the treatment of HCC.