Integrative multi-omics analysis reveals a membrane tension signature associated with tumor-stroma crosstalk in hepatocellular carcinoma

Background Dysregulated membrane tension (MT) drives tumor cell migration, invasion, and immune evasion, yet the prognostic value of MT-related genes (MTRGs) in hepatocellular carcinoma (HCC) remains unclear. Methods We integrated transcriptomic and clinical data from TCGA, ICGC, and GEO. A three-gene MTRG prognostic signature was developed through univariate and LASSO-Cox regression, and validated using Kaplan–Meier analysis, time-dependent ROC curves, and calibration plots. Functional enrichment, immune infiltration, tumor mutational burden, and immunotherapy response was predicted using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Single-cell and spatial transcriptomics were used to investigate the mechanistic role of CFL1 in tumor-stroma crosstalk. Results The signature (CFL1, CRTC2, SRGAP2) stratified HCC patients into high- and low-risk groups with distinct overall survival (OS). High-risk tumors showed coordinated activation of MT and ECM-remodeling pathways alongside an immunosuppressive microenvironment. In silico analyses suggested that CFL1-high tumor cells may transmit MDK signals to fibroblasts (via SDC2, NCL, and ITGA4–ITGB1) and to T cells (via NCL). Spatial transcriptomics confirmed predominant CFL1 enrichment in stromal compartments. The signature was an independent prognostic factor, and the nomogram showed promising clinical utility. Conclusions This three-gene MTRG-associated signature is associated with predicted immunotherapy response based on computational analysis in HCC. Our results suggest a potential link between biophysical MT and tumor stroma co evolution and represent a potential therapeutic direction warranting further experimental validation.