Adv Sci (Weinh). 2026 Sep 27:e78005. doi: 10.1002/advs.78005. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) patients show heterogeneous responses to immune checkpoint inhibitors (ICIs). This study developed ECOS-Net, a transformer-based multitask network integrating CT-derived habitat and 2.5-dimensional (2.5D) deep learning features for simultaneously predicting early disease control (DC) and overall survival (OS). Of 1,234 patients with HCC enrolled from eight institutions and public databases, 832 ICI-treated patients were used for model development. ECOS-Net fused features using multi-head attention and generated early DC probabilities and OS risk scores. ECOS-DC achieved AUCs of 0.836, 0.822, and 0.817 in training, internal validation, and external test sets, outperforming clinical models (all p values < 0.05). ECOS-OS yielded C-indices of 0.730, 0.722, and 0.720, respectively. Integrated models also showed favorable external performance (early DC AUC: 0.825; OS C-index: 0.741). Patients with higher ECOS-DC probabilities had a higher likelihood of early DC, whereas those with higher ECOS-OS risk had shorter OS, with directionally consistent associations across most subgroups. Exploratory biological analyses suggested that the higher ECOS-DC probability and lower ECOS-OS risk groups were associated with immune-active tumor microenvironment features. Therefore, ECOS-Net shows potential as a non-invasive imaging-based risk stratification framework for simultaneously predicting early DC and OS in ICI-treated HCC patients.

PMID:42801546 | PMC:PMC13616327 | DOI:10.1002/advs.78005

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839