ArticleJournal for immunotherapy of cancer2026
Lithocholic acid-activated VDR in macrophages promotes HCC recurrence post-ablation via SOCS3-mediated suppression of CXCL16.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundIncomplete thermal ablation (iTA) for hepatocellular carcinoma (HCC) fosters an immunosuppressive microenvironment driving local recurrence, yet the metabolic cues linking tissue injury to immune evasion remain undefined. Bile acids, particularly lithocholic acid (LCA), are elevated post-ablation, but their functional role in HCC recurrence is unknown. Here, we investigate whether LCA accumulation after iTA promotes tumor recurrence by suppressing antitumor immunity and identify the underlying molecular mechanism.
methodsOrthotopic and subcutaneous HCC models were subjected to iTA. Bile acid metabolomics, multicolor flow cytometry, and immunofluorescence staining were performed. Human residual HCC specimens were analyzed for vitamin D receptor (VDR) expression, macrophage polarization and invariant natural killer T (iNKT) cell density. For mechanistic studies, tumor-associated macrophage (TAM)-specific conditional knockdown of
resultsiTA markedly elevated intrahepatic LCA levels, which correlated with M2-like TAM polarization and reduced iNKT tumor infiltration. LCA functioned as a VDR agonist in TAMs, transcriptionally upregulating suppressor of cytokine signaling 3 (SOCS3) and suppressing C-X-C motif chemokine ligand 16 (CXCL16). This VDR-SOCS3-CXCL16 axis was necessary and sufficient for impaired iNKT chemotaxis, as genetic ablation of VDR or SOCS3 in TAMs restored CXCL16 secretion. Conversely, LCA treatment inhibited iNKT cell chemotaxis and interferon-γ secretion, which were restored by exogenous CXCL16 supplementation. In human residual HCC, post-ablation tissues exhibited M2-like TAM polarization, and VDR
conclusionsWe identify a hitherto unknown metabolic-immune checkpoint: iTA-induced LCA activates macrophage VDR, triggering SOCS3-mediated epigenetic suppression of CXCL16 and evading iNKT surveillance. TUDCA resets this checkpoint by restoring CXCL16 expression and iNKT function. Thus, targeting this axis with TUDCA represents a readily translatable adjunctive strategy to abrogate post-ablation HCC recurrence.
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