Abstract
<jats:p>Purpose: Liver metastases confer poor outcomes and attenuate the benefit of immunotherapy across solid tumors. This study investigated how the hepatic metastatic niche promotes CD8⁺ T cell dysfunction and immunotherapy resistance in small-cell lung cancer (SCLC). Experimental Design: Clinical outcomes and tumor gene expression were integrated with multi-region single-cell RNA sequencing of T cells from rapid-autopsy SCLC metastases, together with spatial transcriptomics. SCLC-hepatocyte conditioned-media models were combined with stable-isotope tracing, mass spectrometry, functional and metabolic assays, and ChIP-qPCR to define mechanisms of CD8⁺ T cell suppression. Results: Liver metastases were associated with inferior survival and reduced benefit from immune checkpoint blockade. Multi-region single-cell analysis showed that CD8⁺ T cells from liver metastases exhibited an exhaustion-associated state enriched for hypoxia, lactate, and TGF-β programs. SCLC-hepatocyte crosstalk generated a lactate- and TGF-β-rich microenvironment that reduced CD8⁺ T cell effector function, proximal T cell receptor signaling, glycolytic fitness, viability, and proliferation. Stable-isotope tracing demonstrated transfer and accumulation of co-culture-derived lactate in recipient CD8⁺ T cells, with limited entry into downstream pyruvate-linked pathways. Lactate accumulation was accompanied by increased H3K18 lactylation at the PDCD1, LAG3, and TGFB1 regulatory loci. In parallel, SCLC-hepatocyte crosstalk increased paracrine TGF-β and activated canonical SMAD2 signaling in CD8⁺ T cells. TGF-β receptor inhibition restored CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β transcriptional program was associated with inferior survival, most strongly in patients with liver metastases. Conclusions: Tumor-hepatocyte crosstalk generates convergent lactate and TGF-β signals that drive CD8⁺ T cell dysfunction in liver metastases. This hepatic immune-metabolic circuit provides a potential mechanism for immunotherapy resistance and supports therapeutic strategies targeting TGF-β signaling in liver-metastatic SCLC.</jats:p>