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

Kazi, A.; Cao, Y.; Mohindroo, C.; Joshi, A.; Zhang, Y.; Huang, Y.; Tabe, C.; Schroeder, B.; Andresson, T.; Sharma, A. K.; Thomas, A.

doi:10.64898/2026.07.30.741857

bioRxiv · 10.64898/2026.07.30.741857

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

Kazi, A.·Cao, Y.·Mohindroo, C.·Joshi, A.·Zhang, Y.·Huang, Y.·Tabe, C.·Schroeder, B.·Andresson, T.·Sharma, A. K.·Thomas, A.

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Abstract

PurposeLiver 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 DesignClinical 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. ResultsLiver 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-{beta} programs. SCLC-hepatocyte crosstalk generated a lactate- and TGF-{beta}-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-{beta} and activated canonical SMAD2 signaling in CD8 T cells. TGF-{beta} receptor inhibition restored CD8 T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-{beta} transcriptional program was associated with inferior survival, most strongly in patients with liver metastases. ConclusionsTumor-hepatocyte crosstalk generates convergent lactate and TGF-{beta} 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-{beta} signaling in liver-metastatic SCLC. Translational RelevancePatients 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-{beta} 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-{beta} activates canonical SMAD signaling and reinforces proliferative dysfunction. TGF-{beta} receptor inhibition restores CD8 T cell proliferation. In the phase III IMpower133 cohort, a combined lactate-TGF-{beta} program is associated with inferior survival, particularly among patients with liver metastases. These findings provide a mechanistic and biomarker framework for testing TGF-{beta}-directed strategies in liver-metastatic SCLC, a population with substantial unmet clinical need.

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Kazi, A., Cao, Y., Mohindroo, C., Joshi, A., Zhang, Y., Huang, Y., Tabe, C., Schroeder, B., Andresson, T., Sharma, A. K., Thomas, A.. 2026-07-31. 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. https://doi.org/10.64898/2026.07.30.741857

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