A multi-scale stress-lactylation blueprint unmasks a macrophage-engineered metabolic trap driving non-canonical CD8⁺ T cell paralysis and dual-targeting vulnerability in hepatocellular carcinoma

Chronic systemic stress (CSS) is associated with the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms linking physiological exhaustion into intratumoral immune evasion remain fundamentally opaque. We aimed to decode the biological axis bridging systemic allostatic load (AL), lactate metabolism, and localized immune collapse. Leveraging the NHANES cohort, we established epidemiological links between AL, lactate, and mortality. An integrative consensus machine-learning framework derived a stress-lactylation signature (SLS). We mapped the SLS-associated microenvironment via single-cell/spatial transcriptomics, dissecting mechanistic interactions through in silico network perturbations and pharmacogenomics, which were subsequently corroborated by comprehensive ex vivo clinical tissue analyses and in vitro functional co-culture validations. High AL independently predicted elevated all-cause mortality in adults with liver dysfunction, correlating robustly with systemic lactate. Projecting this macro-level vulnerability into the tumor microenvironment, we distilled a 6-gene SLS as a potent HCC prognosticator. Multi-omics deconvolution revealed that high-SLS tumors compartmentalize into immunosuppressive niches where SPP1⁺ macrophages mediate the metabolic suppression of CD8⁺ T cells. Crucially, ex vivo analyses of HCC patient tissues verified elevated histone lactylation (H3K9la) and its profound spatial co-localization with active glycolysis (GLUT1⁺) and SPP1⁺ macrophages. Furthermore, in vitro co-culture models confirmed that blocking tumor-derived lactate directly attenuates M2-like polarization and downregulates SPP1 expression in recipient macrophages. Finally, Adavosertib was functionally validated as a precision dual-targeting agent, effectively inhibiting both upstream tumor lactate production and downstream macrophage-associated remodeling ( CTSS ). We delineate a comprehensive multi-scale blueprint linking CSS to localized immune failure. The SLS provides an accurate prognostic tool, while our experimental validations expose a lactate-driven macrophage metabolic trap, unveiling a precision dual-inhibition strategy to reinvigorate anti-tumor immunity in stress-burdened HCC.