Ther Adv Med Oncol. 2026 Aug 31;18:17588359261481797. doi: 10.1177/17588359261481797. eCollection 2026.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) is driven by extensive metabolic reprogramming, vascular remodeling, and immune microenvironmental dysfunction. Although numerous stratification signatures have been proposed, few are grounded in clinically derived serum multi-omics and biologically linked to endothelial remodeling, endothelial regulation, and immune exclusion.
OBJECTIVES: This study aimed to identify a serum-derived lipid-endothelial program associated with immune exclusion and clinical stratification in HCC.
DESIGN: A translational multi-omics study integrating clinically collected serum samples, public transcriptomic cohorts, single-cell RNA sequencing, and experimental validation.
METHODS: Proteomic and metabolomic sequencing was performed on serum samples from patients with HCC and normal controls. Dysregulated pathways were integrated with transcriptomic data from TCGA-LIHC and ICGC-LIRI-JP cohorts to identify genes jointly associated with lipid metabolism and leukocyte transendothelial migration. A risk score was calculated using the expression of PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA. Higher expression of TXNRD1, CLDN4, CLDN6, and CTSA contributed to a higher risk score, whereas PON1 and CYP2C9 contributed protective coefficients. Immune contexture, tumor mutation burden, and exploratory therapeutic sensitivity patterns were further evaluated using transcriptome-based drug sensitivity prediction, followed by single-cell RNA sequencing and experimental expression validation.
RESULTS: Serum multi-omics analysis revealed prominent dysregulation of lipid metabolic pathways and leukocyte transendothelial migration-related processes in HCC. Integrative analysis identified a six-gene lipid-endothelial signature (PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA) that stratified patients into high- and low-risk groups. In the TCGA-LIHC cohort, high-risk patients had significantly poorer overall survival than low-risk patients (log-rank P < 0.0001), and this survival-stratifying association was externally supported in the ICGC-LIRI-JP cohort (log-rank P = 0.016). The high-risk phenotype was associated with immune-excluded features, distinct somatic mutation patterns, and altered predicted sensitivity to several selected anticancer agents. Single-cell analysis and experimental assays further supported the association between the six-gene program, malignant epithelial states, endothelial-related remodeling, and immune microenvironmental heterogeneity.
CONCLUSION: This study defines a clinically derived lipid-endothelial program associated with immune exclusion, adverse prognosis, and potential differences in therapeutic vulnerability in HCC. The proposed signature provides a biologically informed framework for prognostic assessment and may support future evaluation of targeted interventions in HCC.
PMID:42682961 | PMC:PMC13530516 | DOI:10.1177/17588359261481797
Cytokine. 2026 Apr 6;202:157144. doi: 10.1016/j.cyto.2026.157144. Online ahead of print.
ABSTRACT
BACKGROUND: The remodeling of the tumor immune microenvironment (TME) is a pivotal determinant of therapeutic efficacy and clinical outcome in Lung Adenocarcinoma (LUAD). While WNT signaling is a known oncogenic driver, the specific immunomodulatory role of WNT7A and its potential crosstalk with inflammatory pathways in LUAD remain to be fully elucidated. We sought to define the prognostic value of WNT7A and explore the molecular mechanisms by which it may foster an immunosuppressive TME.
METHODS: We performed a multi-omics analysis utilizing the TCGA-LUAD cohort (N = 508) and validated findings in an independent external cohort (GSE30219, N = 293). The prognostic significance of WNT7A was evaluated using Kaplan-Meier and multivariate Cox regression analyses. TME composition was dissected via ssGSEA, focusing on myeloid-derived suppressor cell (MDSC) infiltration. Mechanistic pathways were identified using Gene Set Enrichment Analysis (GSEA) and gene co-expression networks.
RESULTS: High WNT7A expression was identified as a significant predictor of poor Overall Survival (OS) in the TCGA cohort (P < 0.05) and validated in the external cohort (P < 0.05). Multivariate analysis confirmed WNT7A as an independent prognostic risk factor (HR = 1.085, P = 0.036). Immunologically, WNT7A expression was positively correlated with MDSC infiltration (R = 0.43, P < 0.001), suggesting a shift towards an immune-tolerant phenotype. Mechanistically, GSEA revealed a robust activation of inflammatory signaling in the high-WNT7A group. Specifically, the TNFA Signaling via NF-κB pathway was significantly enriched(NES = 2.52, P < 0.001). Consistent with this pathway activation, WNT7A showed a statistically significant positive correlation with CCL2 (P < 0.001), a critical chemokine for MDSC recruitment, implicating the NF-κB/CCL2 axis in this process.
CONCLUSION: WNT7A serves as a prognostic biomarker linked to immune evasion in LUAD, potentially by modulating the NF-κB/CCL2/MDSC axis. This study identifies WNT7A as a potential therapeutic target to remodel the immune microenvironment, providing a rationale for future investigations into WNT-targeted strategies to improve immunotherapy efficacy.
PMID:41946008 | DOI:10.1016/j.cyto.2026.157144
Cytokine. 2026 Apr 6;202:157144. doi: 10.1016/j.cyto.2026.157144. Online ahead of print.
ABSTRACT
BACKGROUND: The remodeling of the tumor immune microenvironment (TME) is a pivotal determinant of therapeutic efficacy and clinical outcome in Lung Adenocarcinoma (LUAD). While WNT signaling is a known oncogenic driver, the specific immunomodulatory role of WNT7A and its potential crosstalk with inflammatory pathways in LUAD remain to be fully elucidated. We sought to define the prognostic value of WNT7A and explore the molecular mechanisms by which it may foster an immunosuppressive TME.
METHODS: We performed a multi-omics analysis utilizing the TCGA-LUAD cohort (N = 508) and validated findings in an independent external cohort (GSE30219, N = 293). The prognostic significance of WNT7A was evaluated using Kaplan-Meier and multivariate Cox regression analyses. TME composition was dissected via ssGSEA, focusing on myeloid-derived suppressor cell (MDSC) infiltration. Mechanistic pathways were identified using Gene Set Enrichment Analysis (GSEA) and gene co-expression networks.
RESULTS: High WNT7A expression was identified as a significant predictor of poor Overall Survival (OS) in the TCGA cohort (P < 0.05) and validated in the external cohort (P < 0.05). Multivariate analysis confirmed WNT7A as an independent prognostic risk factor (HR = 1.085, P = 0.036). Immunologically, WNT7A expression was positively correlated with MDSC infiltration (R = 0.43, P < 0.001), suggesting a shift towards an immune-tolerant phenotype. Mechanistically, GSEA revealed a robust activation of inflammatory signaling in the high-WNT7A group. Specifically, the TNFA Signaling via NF-κB pathway was significantly enriched(NES = 2.52, P < 0.001). Consistent with this pathway activation, WNT7A showed a statistically significant positive correlation with CCL2 (P < 0.001), a critical chemokine for MDSC recruitment, implicating the NF-κB/CCL2 axis in this process.
CONCLUSION: WNT7A serves as a prognostic biomarker linked to immune evasion in LUAD, potentially by modulating the NF-κB/CCL2/MDSC axis. This study identifies WNT7A as a potential therapeutic target to remodel the immune microenvironment, providing a rationale for future investigations into WNT-targeted strategies to improve immunotherapy efficacy.
PMID:41946008 | DOI:10.1016/j.cyto.2026.157144
Oncogene, Published online: 04 April 2026; doi:10.1038/s41388-026-03766-0
S100A6 promotes liver metastasis by activating FGFR3 signaling in BAP1-deficient uveal melanoma
npj Digital Medicine, Published online: 02 April 2026; doi:10.1038/s41746-026-02572-y
Integrating large language models for enhanced predictive analytics in healthcare
Nature, Published online: 31 March 2026; doi:10.1038/s41586-026-10442-6
Structure of the mouse cytoplasmic lattice
Curr Med Chem. 2026 Mar 17. doi: 10.2174/0109298673415187251212085809. Online ahead of print.
ABSTRACT
BACKGROUND: Solanum incanum L. (S. incanum) is a Traditional Chinese Medicine (TCM) known for its heat-clearing and detoxifying properties. This study evaluates the anti-cancer potential of S. incanum in lung and colorectal adenocarcinoma. Also, we aim to confirm the connection between the lung and the large intestine, as proposed in TCM theory.
METHODS: This study employed network pharmacology analysis, MTT and morphological analysis, Western blotting, and molecular docking to investigate the anti-cancer effects of S. incanum, particularly through its activation of the TRAIL-mediated extrinsic apoptotic pathway.
RESULTS: This study identified 15 active compounds in S. incanum, with glycosylated alkaloids such as α-solanine and solasonine highlighted as key bioactive compounds. KEGG and GO analyses revealed that S. incanum influences apoptosis-related pathways, particularly the extrinsic apoptotic pathway, regulating mediators such as CASP3, CASP8, and various TNF- related receptors. The anticancer potential was assessed through cellular studies using A549 and HT29 cell lines, with MTT cell viability assays showing that α-solanine induces apoptosis, with IC50 values between 20 and 30 μM. Western blot analysis demonstrated that S. incanum activates apoptosis via the TRAIL-mediated extrinsic apoptotic pathway, promoting CASP8, CASP3, and PARP1 cleavage in a dose-dependent manner, affecting DNA synthesis. Molecular docking further identified α-solanine and solasonine as compounds that bind to critical proteins in the TRAIL-related apoptotic pathway, confirming their roles in promoting apoptosis.
DISCUSSION: The shared activation of the TRAIL-mediated apoptotic pathway in both lung and colorectal adenocarcinoma models suggests a common molecular mechanism. These findings provide experimental evidence linking traditional ethnopharmacological concepts with apoptosis-related anti-cancer activity.
CONCLUSIONS: This study emphasizes that the main compound of S. incanum, α-solanine, supports the ethnopharmacological concept of "Exterior-interior Pairing of the Lung and Large Intestine", thereby demonstrating that both lung and colorectal adenocarcinomas share a common anticancer pathway through a TRAIL-related apoptotic mechanism.
PMID:41863159 | DOI:10.2174/0109298673415187251212085809
Am J Surg Pathol. 2026 Jun 1;50(6):695-704. doi: 10.1097/PAS.0000000000002533. Epub 2026 Mar 13.
ABSTRACT
With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.
PMID:41821426 | DOI:10.1097/PAS.0000000000002533
Am J Surg Pathol. 2026 Mar 13. doi: 10.1097/PAS.0000000000002533. Online ahead of print.
ABSTRACT
With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.
PMID:41821426 | DOI:10.1097/PAS.0000000000002533
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