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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. IFN\u03b3-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 IFN\u03b3-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\u2019 g\u2009=\u20090.10, 95% CI \u22120.42 to 0.61) and did not establish clinical response prediction. These results support a structured IFN\u03b3-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.<\/jats:p>","DOI":"10.1371\/journal.pone.0359327","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:39:16Z","timestamp":1791308356000},"page":"e0359327","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated multi-omic analysis characterizes an IFN\u03b3-responsive-to-myeloid-suppressive immune continuum in immune-active hepatocellular carcinoma"],"prefix":"10.1371","volume":"21","author":[{"given":"Luping","family":"Lin","sequence":"first","affiliation":[{"name":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","place":["Fuzhou, China"],"department":["Department of Hepatobiliary and Pancreatic 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