Research progress on immune tolerance mechanisms in liver metastatic tumors and the “Liver-metastasis-oriented shared-mechanism therapeutic strategy” approach

Abstract Liver metastases pose a serious challenge in the field of systemic cancer treatment, as this organ has a particular microenvironment that favours malignant cells disseminating to settle there. We outline major steps of liver immune tolerance in metastasis including pre-metastatic niche formation, immune evasion during circulation, establishment of an intrahepatic immune desert and metabolism, myeloid cell networks and gut microbiome-mediated coordinated tolerance. We then combine new combination and integrative therapies that are intended to break this tolerance; these include immunochemotherapy regimens, synergistic antiangiogenics and immunotherapies, dual immune checkpoint blockade and myeloid-cell reprogramming, combined locoregional and systemic therapies and new microenvironmental targeting. Each strategy is assessed with regard to its potential disruption of hepatic immune quiescence, improved clinical translation and durable antitumour activity. We suggest a proposed solution termed Liver-metastasis-oriented shared-mechanism therapeutic strategy, which may target multiple metastatic bottlenecks due to similarities. This framework provides a basis for personalizing combination therapies and designing future clinical trials for treating liver metastases, with organ-specific considerations and will be the subject of a commentary.