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Preprint WatchModerateAugust 1st, 2026

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.

Hepatocyte-derived lactate drives H3K18 lactylation at the PDCD1, LAG3 and TGFB1 regulatory loci, inducing a CD8 T cell exhaustion state that confers resistance to immune checkpoint blockade.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint places LAG3 downstream of a metabolic program in the hepatic niche rather than upstream of it, which matters for both LAG3 failures on the Claidex record. The eftilagimod alfa Phase 2/3 in HER2-negative metastatic breast cancer (eftilagimod-alfa-lag3-her2-negative-metastatic-breast-cancer-aipac-003-phase2-3-sponsor-termination) tested an MHC class II agonist intended to prime an antigen presenting cell response, and the favezelimab Phase 1/2 in Hodgkin and B-cell lymphoma (favezelimab-lag3-hodgkin-lymphoma-mk-4280-003-phase1-2-strategic-termination) tested checkpoint blockade of the same receptor. Neither program stratified patients by the metabolic state of the metastatic niche. If LAG3 expression is an epigenetic readout of lactate exposure, then agents acting at the receptor may be treating a marker of an upstream metabolic constraint, and trials that do not measure or modify that constraint will see the same signal in responders and non-responders. The claim is preclinical and the tumour type differs from both recorded failures, so this is a design flag rather than a contradiction.

Abstract excerpt

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-{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. Conclusions: Tumor-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.

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2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.