Liver metastasis resists immunotherapy via GPR171-mediated dysfunction T cells in the tumor immunosuppression microenvironment

Background This study investigated the immune features of liver metastasis (LM) and evaluated GPR171 inhibition as a potential strategy to improve the response to PD-L1 blockade. Results Analyses of in-house cohorts comprising 45 patients with metastatic colorectal cancer and 145 patients with metastatic lung cancer treated with anti-PD1/PDL1 inhibitors associated LM with poorer outcomes than other metastatic patterns. Multi-omics analyses identified differences in immune-cell composition and inferred cell communication, with GPR171 emerging as a candidate associated with altered T-cell states. In mice bearing subcutaneous and intrahepatic MC38 tumors, GPR171 antagonist treatment combined with anti-PDL1 was associated with reduced subcutaneous tumor growth, increased CD8+ T-cell proportions in subcutaneous tumors, changes in liver-associated myeloid populations, and higher plasma IFN-γ levels. Checkpoint-associated lymphocyte phenotypes also changed, but their functional significance remains unresolved. Conclusion The findings support further investigation of GPR171 inhibition in the setting of liver metastases. The combination treatment was associated with subcutaneous tumor control in mice bearing concomitant intrahepatic tumors. The observed immune phenotypes do not establish a cell-specific mechanism or a clinical treatment benefit.