Tumor-hepatocyte crosstalk drives a hepatic lactate-TGF-β axis of CD8 + T cell exhaustion and immunotherapy resistance in small-cell lung cancer liver metastases.

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. TRANSLATIONAL RELEVANCE: Patients with SCLC liver metastases have poor outcomes and derive limited benefit from immune checkpoint blockade, but actionable mechanisms of hepatic immune resistance remain undefined. We identify an immune-metabolic circuit in which SCLC-hepatocyte crosstalk generate lactate and TGF-β signals that converge on CD8⁺ T cells. Stable-isotope tracing demonstrates the transfer and accumulation of tumor-hepatocyte-derived lactate in recipient T cells, which causes H3K18 lactylation at exhaustion- and TGFB1-associated loci. In parallel, paracrine TGF-β activates canonical SMAD signaling and reinforces proliferative dysfunction. TGF-β receptor inhibition restores CD8⁺ T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-β program is associated with inferior survival, particularly among patients with liver metastases. These findings provide a mechanistic and biomarker framework for testing TGF-β-directed strategies in liver-metastatic SCLC, a population with substantial unmet clinical need.