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

Front Immunol. 2026 May 8;17:1780459. doi: 10.3389/fimmu.2026.1780459. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) have transformed the management of advanced lung cancer, yet most patients experience primary resistance, hyperprogressive disease (HPD), or clinically significant immune-related adverse events (irAEs). Multi-omics technologies now enable integrated interrogation of tumor, microenvironmental, host, and clinical determinants of these divergent outcomes. In this review, we first discuss the biological and clinical foundations of PD-1/PD-L1 blockade in non-small cell and small cell lung cancer, and summarize the spectrum of resistance, HPD, and irAEs observed in trials and real-world practice. We then describe multi-omics study frameworks that connect genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and microbiome profiling with these outcome phenotypes. Building on this foundation, we synthesize evidence for composite biomarkers of primary and acquired resistance, delineate emerging multi-omics signatures of HPD, and examine host- and tumor-derived multi-omics correlates of organ-specific and systemic irAEs. We further propose an efficacy-risk quadrant framework to guide clinical decision-making when favorable efficacy predictors coexist with elevated risk of severe adverse outcomes, and outline a three-step approach for high-efficacy/high-risk patients: joint probability reporting, multi-omics guided mitigation, and dynamic reassessment. Finally, we evaluate translational strategies that integrate multi-omics scores into baseline risk stratification, dynamic monitoring with attention to technical challenges such as distinguishing true progression from ctDNA pseudoprogression, and biomarker-driven trial design, while assessing the evidence level and translational readiness of candidate assays from retrospective discovery to clinical implementation. A clinical case illustrates how multi-omics can link baseline risk stratification, regimen selection, and longitudinal monitoring into a coherent action plan, while acknowledging that artificial intelligence-driven models remain investigational and real-world application still relies on clinician judgment. Collectively, this review defines how integrated multi-omics biomarkers can be leveraged to predict resistance, HPD, and immune-related toxicity, and to refine patient selection and management during PD-1/PD-L1 therapy in lung cancer.

PMID:42183274 | PMC:PMC13194140 | DOI:10.3389/fimmu.2026.1780459