Multiregional profiling reveals <i>THBS1</i>-<i>SPP1</i> monocyte-macrophage axis drives immunosuppression and outcome in colorectal liver metastases.

Abstract

Colorectal cancer (CRC) commonly metastasizes to the liver (CRLM), where it is the leading cause of CRC-related deaths. While immune checkpoint therapies show promise, their effectiveness is limited in CRLM due to the immunosuppressive liver tumor microenvironment (TME). Using multiregional tissue sampling from CRLM patient samples, we identified distinct immune zones within CRLM. Active Granzyme⁺CD8⁺ T cells were found in normal liver tissue, while CD8⁺ T cells in the tumor core were dysfunctional. At the tumor margin, we observed a pre-exhausted immune zone enriched in <i>THBS1⁺</i> monocytes and CD47<i>⁺</i>CD8<i>⁺</i> T cells. Trajectory analysis showed that <i>THBS1⁺</i> monocytes differentiate into <i>SPP1⁺</i> macrophages, which accumulate in the tumor core and promote immune suppression via <i>TIM-3</i> and <i>CTLA-4</i> on exhausted CD8⁺ T cells. The presence of <i>SPP1⁺</i> macrophages correlates with increased T cell exhaustion and poor survival, suggesting them as potential targets to restore antitumor immunity in CRLM.