Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Environ Int. 2026 Apr 8;210:110249. doi: 10.1016/j.envint.2026.110249. Online ahead of print.

ABSTRACT

BACKGROUND: Deoxynivalenol (DON), a prevalent food-borne mycotoxin, increasingly recognized as a potent driver in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma (HCC); however, its systematic role is unclear. This study aims to decode the pathogenic networks of DON through an integrated multi-omics and toxicological framework.

METHODS: We integrated transcriptomic datasets from public repositories (GSE139602 and GSE25097) and single-cell RNA-seq data (GSE136103 and GSE149614) with toxicogenomics data. Analytical approaches included differential expression analysis, protein-protein interaction networks, profiling, single-cell trajectory analysis, trend testing, and machine learning modeling, and molecular docking. Key findings were validated through in vitro assays in human hepatocytes (THLE-2), as well as in vivo mouse models.

RESULTS: Five core hub genes (FAT1, CCND1, FOS, GADD45G, and PHLDA1) were identified as consistent drivers of DON-induced liver injury progression. Longitudinal analysis revealed that FAT1 and CCND1 underwent progressive upregulation, while GADD45G, and PHLDA1 were significantly suppressed across disease stages. Molecular docking and Cellular Thermal Shift Assays (CETSA) provided physical evidence of direct binding between DON and these hub proteins. Furthermore, prolonged DON exposure induced significant G2/M phase arrest in hepatocytes, consistent with the sustained dysregulation of the GADD45G/CCND1 axis. In vivo results corroborated that DON triggers noticeable hepatic structural damage and inflammatory infiltration, synchronized with hub protein dysregulation.

CONCLUSION: Chronic DON exposure drives liver disease progression by dysregulating core molecular networks and direct interaction with key hub proteins. Our integrated approach provides novel mechanistic insights and highlights potential biomarkers for DON-induced hepatotoxicity.

PMID:41967175 | DOI:10.1016/j.envint.2026.110249

Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Environ Int. 2026 Apr 8;210:110249. doi: 10.1016/j.envint.2026.110249. Online ahead of print.

ABSTRACT

BACKGROUND: Deoxynivalenol (DON), a prevalent food-borne mycotoxin, increasingly recognized as a potent driver in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma (HCC); however, its systematic role is unclear. This study aims to decode the pathogenic networks of DON through an integrated multi-omics and toxicological framework.

METHODS: We integrated transcriptomic datasets from public repositories (GSE139602 and GSE25097) and single-cell RNA-seq data (GSE136103 and GSE149614) with toxicogenomics data. Analytical approaches included differential expression analysis, protein-protein interaction networks, profiling, single-cell trajectory analysis, trend testing, and machine learning modeling, and molecular docking. Key findings were validated through in vitro assays in human hepatocytes (THLE-2), as well as in vivo mouse models.

RESULTS: Five core hub genes (FAT1, CCND1, FOS, GADD45G, and PHLDA1) were identified as consistent drivers of DON-induced liver injury progression. Longitudinal analysis revealed that FAT1 and CCND1 underwent progressive upregulation, while GADD45G, and PHLDA1 were significantly suppressed across disease stages. Molecular docking and Cellular Thermal Shift Assays (CETSA) provided physical evidence of direct binding between DON and these hub proteins. Furthermore, prolonged DON exposure induced significant G2/M phase arrest in hepatocytes, consistent with the sustained dysregulation of the GADD45G/CCND1 axis. In vivo results corroborated that DON triggers noticeable hepatic structural damage and inflammatory infiltration, synchronized with hub protein dysregulation.

CONCLUSION: Chronic DON exposure drives liver disease progression by dysregulating core molecular networks and direct interaction with key hub proteins. Our integrated approach provides novel mechanistic insights and highlights potential biomarkers for DON-induced hepatotoxicity.

PMID:41967175 | DOI:10.1016/j.envint.2026.110249

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1α/PPARα and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARα, PGC-1α, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARα /PGC-1α and FXR-BSEP signaling pathway, promotes fatty acid β oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARα /PGC-1α pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid β-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

Phytomedicine. 2026 Mar 30;155:158128. doi: 10.1016/j.phymed.2026.158128. Online ahead of print.

ABSTRACT

BACKGROUND: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and its pathogenesis is complex, creating an urgent need to discover novel and effective therapeutic strategies. The Zuogui Jiangtang Qinggan formula (ZGJTQGF), an approved in-hospital preparation, has demonstrated significant clinical efficacy in treating diabetes over several decades. However, the mechanisms underlying its potential therapeutic effects on MASLD remain unclear PURPOSE: This study systematically investigates the therapeutic effects and molecular mechanisms of ZGJTQGF on MASLD through the integration of network pharmacology and multi-omics strategies.

METHODS: The model of MASLD was successfully induced in db/db mice by a high-fat diet (HFD), which displayed characteristic dyslipidaemia. Serum biomarkers, histology, and hepatic multi-omics analyses were employed to assess metabolic status, steatosis, targets, and pathways. Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), molecular docking analysis and in vitro verification were applied to explore the active ingredients of ZGJTQGF.

RESULTS: ZGJTQGF significantly reduced dyslipidemia in HFD-fed mice, inhibited pro-inflammatory cytokines, and restored glucose metabolic balance by lowering levels of glucose, insulin, OGTT, and HOMA-IR. Histopathology showed reduced lipid deposition and hepatocyte damage. Comprehensive multi-omics analysis suggested that regulating the AMPK/PGC-1α/PPARα and FXR-BSEP signaling pathways could be potential targets for ZGJTQGF in reprogramming glucose and lipid metabolism in MASLD treatment. Blood component analysis identified 52 ZGJTQGF-derived compounds. In molecular docking experiments, Wogonin, Naringenin, Quercetin, Tanshinone IIA and Berberine showed high-affinity binding to core targets in AMPK, PPARα, PGC-1α, FXR and FAS. Mechanistically, ZGJTQGF activated AMPK/PPARα /PGC-1α and FXR-BSEP signaling pathway, promotes fatty acid β oxidation and enhances energy consumption in AML-2 and 3T3-L1 cells, downregulates SREBP-1-dependent adipogenesis (reduces ACC1 and FAS expression), alleviates MASLD driven reprogramming of glucose and lipid metabolism, and regulates lipid metabolism and fatty acid synthesis.

CONCLUSIONS: ZGJTQGF activates the AMPK/PPARα /PGC-1α pathway and inhibits abnormal lipid accumulation in diabetic fatty liver by promoting fatty acid β-oxidation, energy consumption, and bile acid metabolism. These findings provide new insights into the mechanism of ZGJTQGF in the treatment of diabetic fatty liver disease.

PMID:41962267 | DOI:10.1016/j.phymed.2026.158128

Immunity. 2026 Apr 8:S1074-7613(26)00075-0. doi: 10.1016/j.immuni.2026.02.005. Online ahead of print.

ABSTRACT

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

PMID:41956098 | DOI:10.1016/j.immuni.2026.02.005

Acta Biochim Biophys Sin (Shanghai). 2026 Mar 25. doi: 10.3724/abbs.2025238. Online ahead of print.

ABSTRACT

The environmental pollutant benzo(a)pyrene (B(a)P), a representative polycyclic aromatic hydrocarbon (PAH), is a recognized carcinogen, and chronic pulmonary inflammation is closely associated with lung carcinogenesis. Although alveolar type 2 (AT2) cells are the origin of lung adenocarcinoma, the genetic and functional changes in AT2 cells and the mechanisms involved in inflammation-related lung tumorigenesis have not been elucidated. Here, C57BL/6J mice are exposed to B(a)P and the inflammatory irritant lipopolysaccharide (LPS) to establish a model of inflammation-related lung tumorigenesis. Single-cell RNA sequencing is performed on lung tissues. DNA mutations in AT2 cells are analyzed via whole-exome sequencing. The protein expression of AT2 cells in lung cancer tissue is determined by immunofluorescence staining. The results reveal that LPS promotes B(a)P-induced lung tumorigenesis; in the whole lungs of B(a)P/LPS, a decreased proportion, altered differentiation trajectory, and increased gene mutation number in AT2 cells are observed. Additionally, in B(a)P/LPS-treated lung cancer tissue, the levels of γ-H2AX DNA damage and the proliferation marker Ki67 in AT2 cells are increased, whereas the levels of differentiation markers are decreased. Single-cell RNA transcriptomics reveals that the autophagy-related genes Foxo3 and Ppp2r5, which are enriched in the PI3K-Akt pathway, and the autophagy-related genes in AT2 cells in lung cancer are decreased in the B(a)P/LPS group. Thus, chronic inflammation promotes DNA damage, gene mutation and dysfunction in AT2 cells, and decreased autophagy in AT2 cells may be an important mechanism for inflammation-related lung tumorigenesis.

PMID:41952558 | DOI:10.3724/abbs.2025238

Front Genet. 2026 Mar 23;16:1722368. doi: 10.3389/fgene.2025.1722368. eCollection 2025.

ABSTRACT

Lung cancer is one of the most common cancers worldwide and one of the leading causes of cancer death, with a heavy disease burden and severe public health challenges. Multi-omics techniques, such as genomics, proteomics, metabolomics, and radiomics, play a crucial role in the early diagnosis and treatment of lung cancer, revealing the molecular characteristics and mechanisms of lung cancer, and have significant clinical application value. However, it also faces numerous challenges, such as data issues, "black box" problems, and ethical and legal concerns. How to leverage strengths while mitigating weaknesses, achieve clinical translation of technology, and serve patients more effectively deserves our deep reflection. This article reviews the specific applications and challenges of multi-omics methods in lung cancer research and personalized treatment.

PMID:41948518 | PMC:PMC13050793 | DOI:10.3389/fgene.2025.1722368

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790