Lithocholic acid-activated VDR in macrophages drives HCC recurrence post-ablation by suppressing CXCL16

Incomplete thermal ablation (iTA) for hepatocellular carcinoma (HCC) often leads to local recurrence due to an immunosuppressive microenvironment. The specific metabolic signals linking this tissue injury to immune evasion remain poorly understood. Bile acids, particularly lithocholic acid (LCA), are known to be elevated post-ablation, but their direct role in driving HCC recurrence and modulating the immune response, specifically via the vitamin D receptor (VDR) pathway in macrophages, has been an undefined gap.

Researchers utilized orthotopic and subcutaneous HCC models subjected to incomplete thermal ablation (iTA). They performed bile acid metabolomics, multicolor flow cytometry, and immunofluorescence staining to analyze the tumor microenvironment. Human residual HCC specimens were examined for VDR expression, macrophage polarization, and invariant natural killer T (iNKT) cell density. For mechanistic studies, tumor-associated macrophage (TAM)-specific conditional knockdown of Vdr or Socs3 was employed, alongside iNKT cell co-culture systems. The therapeutic potential of tauroursodeoxycholic acid (TUDCA), a bile acid modulator, was evaluated in vivo.

Post-iTA, intrahepatic LCA levels were markedly elevated, correlating with M2-like TAM polarization and reduced iNKT tumor infiltration. LCA acted as a VDR agonist in TAMs, leading to the transcriptional upregulation of suppressor of cytokine signaling 3 (SOCS3) and suppression of C-X-C motif chemokine ligand 16 (CXCL16). This VDR-SOCS3-CXCL16 axis was found to be necessary and sufficient for impaired iNKT chemotaxis. Genetic ablation of VDR or SOCS3 in TAMs restored CXCL16 secretion. Conversely, LCA treatment inhibited iNKT cell chemotaxis and interferon-γ secretion, effects that were restored by exogenous CXCL16 supplementation. In human residual HCC, post-ablation tissues exhibited M2-like TAM polarization, and VDR+ TAM density inversely correlated with intratumoral iNKT cells. Pharmacological intervention with TUDCA remodeled the bile acid pool, suppressing recurrence.