Integrated multi-omic analysis characterizes an IFNγ-responsive-to-myeloid-suppressive immune continuum in immune-active hepatocellular carcinoma
- 1Department of Hepatobiliary and Pancreatic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- 2Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
Abstract
Immune-active hepatocellular carcinoma (HCC) is commonly treated as a single inflamed phenotype, although its internal immune heterogeneity remains incompletely defined. We integrated public bulk transcriptomic, single-cell, spatial transcriptomic, proteomic, phosphoproteomic, and treatment-cohort data to test whether this heterogeneity is better represented by discrete states or a continuous immune axis. In 112 checkpoint-high TCGA-LIHC tumors, an inflamed-minus-myeloid axis showed structured heterogeneity but no robust empirical bimodality: the observed kernel-density curve had one prominent mode and none of 1,000 bootstrap resamples contained two or more prominent modes. IFNγ-responsive-associated and myeloid-suppressive-associated labels were therefore retained only as operational summaries of opposing axis tendencies, and the biological polarity persisted across alternative definitions of immune-active entry. A fixed 10-gene within-sample rank template-contrast score transferred the axis to independent HCC cohorts. Transcriptomic analyses based on gene sets non-overlapping with the compact panel and original state-defining genes supported the IFNγ-oriented end, whereas spatial analyses showed local cross-end coexistence with reduced immediate-neighbor mixing relative to a count-preserving random-label null, and paired proteomic/phosphoproteomic analyses showed concordant myeloid-oriented associations involving macrophage, fibroblast/extracellular-matrix, hypoxia, SPP1-integrin-FAK, and myeloid-receptor programs. Direct application of the frozen transfer score to four public HCC immunotherapy cohorts yielded heterogeneous, imprecise response associations (pooled Hedges’ g = 0.10, 95% CI −0.42 to 0.61) and did not establish clinical response prediction. These results support a structured IFNγ-responsive-to-myeloid-suppressive continuum within immune-active HCC. The framework is transferable across public datasets but requires prospective HCC-specific clinical validation, while functional perturbation studies are needed before causal or therapeutic claims.
Related
- A macrophage-associated immunosuppressive subtype defined by Lactobacillus/Bifidobacterium-associated host genes characterizes prognosis and the immune microenvironment in hepatocellular carcinoma.
- Integrated genomic, transcriptomic, and proteomic analyses prioritize cadmium-responsive class III peroxidases in Salix variegata
- An integrated Phase II/III randomized study comparing durvalumab and tremelimumab ± Hepatic ArteriaL infusion chemotherapy with GEMOX in hepatocellular Carcinoma with high tumor burdEn – ALICE (PRODIGE89 – UCGI44 – ALICE)
- Integrated computational analysis prioritizes candidate targets and pathways linking ochratoxin A exposure to hepatocellular carcinoma
- Second-line treatment selection for advanced hepatocellular carcinoma: a network meta-analysis with reconstructed survival curves and integrated benefit–risk assessment
BibTeX
@article{lin2026integrated,
title = {{Integrated multi-omic analysis characterizes an IFNγ-responsive-to-myeloid-suppressive immune continuum in immune-active hepatocellular carcinoma}},
author = {Luping Lin and Ningna Weng and Huaying Lai and Guangfeng Wu and Jinfeng Lin and Xinjian Wu and Sha Huang and Xiao Chen},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359327},
url = {https://doi.org/10.1371/journal.pone.0359327},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated multi-omic analysis characterizes an IFNγ-responsive-to-myeloid-suppressive immune continuum in immune-active hepatocellular carcinoma
AU - Luping Lin
AU - Ningna Weng
AU - Huaying Lai
AU - Guangfeng Wu
AU - Jinfeng Lin
AU - Xinjian Wu
AU - Sha Huang
AU - Xiao Chen
PY - 2026
DA - 2026/10/06
JO - PLOS One
DO - 10.1371/journal.pone.0359327
UR - https://doi.org/10.1371/journal.pone.0359327
AB - Immune-active hepatocellular carcinoma (HCC) is commonly treated as a single inflamed phenotype, although its internal immune heterogeneity remains incompletely defined. We integrated public bulk transcriptomic, single-cell, spatial transcriptomic, proteomic, phosphoproteomic, and treatment-cohort data to test whether this heterogeneity is better represented by discrete states or a continuous immune axis. In 112 checkpoint-high TCGA-LIHC tumors, an inflamed-minus-myeloid axis showed structured heterogeneity but no robust empirical bimodality: the observed kernel-density curve had one prominent mode and none of 1,000 bootstrap resamples contained two or more prominent modes. IFNγ-responsive-associated and myeloid-suppressive-associated labels were therefore retained only as operational summaries of opposing axis tendencies, and the biological polarity persisted across alternative definitions of immune-active entry. A fixed 10-gene within-sample rank template-contrast score transferred the axis to independent HCC cohorts. Transcriptomic analyses based on gene sets non-overlapping with the compact panel and original state-defining genes supported the IFNγ-oriented end, whereas spatial analyses showed local cross-end coexistence with reduced immediate-neighbor mixing relative to a count-preserving random-label null, and paired proteomic/phosphoproteomic analyses showed concordant myeloid-oriented associations involving macrophage, fibroblast/extracellular-matrix, hypoxia, SPP1-integrin-FAK, and myeloid-receptor programs. Direct application of the frozen transfer score to four public HCC immunotherapy cohorts yielded heterogeneous, imprecise response associations (pooled Hedges’ g = 0.10, 95% CI −0.42 to 0.61) and did not establish clinical response prediction. These results support a structured IFNγ-responsive-to-myeloid-suppressive continuum within immune-active HCC. The framework is transferable across public datasets but requires prospective HCC-specific clinical validation, while functional perturbation studies are needed before causal or therapeutic claims.
SN - 1932-6203
ER -