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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Pengfei Zhu1
  • Pengcheng Zhu2
  • Zijuan Zhu3
  • Gaozhong Bian3
  • Yungang Liu4
  • Qifan Yang5
  • Peipei Luo5
5 affiliations
  1. 1Hebei Medical University
  2. 2Hangzhou Dianzi University
  3. 3The Second Affiliated Hospital of Bengbu Medical College
  4. 4Department of Oncology, Wujin Hospital Affiliated with Jiangsu University
  5. 5Department of Gastroenterology, Wujin Hospital Affiliated with Jiangsu University
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhu2026integrative,
  title = {{Integrative multi-omics analysis reveals a membrane tension signature associated with tumor-stroma crosstalk in hepatocellular carcinoma}},
  author = {Pengfei Zhu and Pengcheng Zhu and Zijuan Zhu and Gaozhong Bian and Yungang Liu and Qifan Yang and Peipei Luo},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1978174},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978174/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Integrative multi-omics analysis reveals a membrane tension signature associated with tumor-stroma crosstalk in hepatocellular carcinoma
AU  - Pengfei Zhu
AU  - Pengcheng Zhu
AU  - Zijuan Zhu
AU  - Gaozhong Bian
AU  - Yungang Liu
AU  - Qifan Yang
AU  - Peipei Luo
PY  - 2026
DA  - 2026/10/05
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1978174
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978174/full
AB  - 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.
SN  - 1664-3224
ER  -