ArticleTranslational oncology2026
Single-cell spatial landscape of aggrephagy activity stratifies hepatocellular carcinoma neutrophils and delivers a 5-gene diagnostic panel for patient stratification.
Article in Translational oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Unveiling the power of TIIC: A prognostic tool for esophageal adenocarcinoma.Translational oncology · 2026Article
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Abstract
backgroundHepatocellular carcinoma (LIHC) features a complex tumor microenvironment (TME) where tumor-associated neutrophils (TANs) show significant plasticity. The role of aggrephagy-selective autophagy of protein aggregates-in shaping neutrophil heterogeneity and LIHC progression remains poorly understood.
methodsWe integrated scRNA-seq (183,671 cells), spatial transcriptomics, and bulk datasets (TCGA, GSE39791). Neutrophils (n=12,547) were re-clustered into six subsets, and aggrephagy activity was quantified via UCell scores. Analysis included pseudotime trajectories, cell-cell communication, metabolic scoring, and machine-learning-based feature selection, followed by in vitro functional validation.
resultsAggrephagy activity was significantly elevated in tumor tissues compared with adjacent normal tissues (P < 0.001) and showed strong cell-type specificity, with TANs among the most enriched populations. High-aggrephagy neutrophils exhibited an undifferentiated state, preferential tumor enrichment, and a positive correlation with transcriptomic risk scores. Trajectory analysis positioned these cells at an early differentiation branch and revealed dominant neutrophil-to-stroma signaling through the CCL3-CCR1, SPP1-CD44, and ANXA1-FPR1 axes. Metabolically, high-aggrephagy neutrophils displayed enhanced inflammatory and epithelial mesenchymal-transition programs alongside suppressed oxidative phosphorylation. Integrative network analysis identified a five-gene diagnostic panel (SQSTM1, WDFY3, DOCK4, CD177, LIMK2) with robust performance across bulk cohorts (AUC 0.83-0.91). Among these, LIMK2 marked a highly interactive neutrophil subset and functionally promoted tumor cell proliferation, survival, migration, and invasion in vitro.
conclusionAggrephagy is associated with a pro-tumorigenic, metabolically reprogrammed neutrophil state in LIHC. The LIMK2-centered gene panel provides a robust framework for subset identification and nominates candidate targets for future autophagy- and neutrophil-directed studies.
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