Immunotherapy in liver metastases: Challenges, emerging evidence, and future directions

Liver metastases are common in advanced cancer and are consistently associated with poorer survival and limited treatment options. Although immunotherapy has transformed outcomes for many malignancies, patients with liver involvement respond less well, highlighting the liver as a uniquely challenging site for effective antitumor immunity. In this review, we examine the biological features that make the liver especially permissive to metastatic growth and immune escape. We first describe the liver’s distinctive anatomy and immune environment, including its dual blood supply, specialized sinusoidal vasculature, and intrinsic immune tolerance. We then discuss how primary tumors actively condition the liver before metastatic seeding through pre-metastatic niche formation driven by tumor-derived cytokines, chemokines, extracellular vesicles, and metabolic signals. A major focus is the dynamic crosstalk between metastatic tumor cells and liver-resident populations, including Kupffer cells, hepatic stellate cells, hepatocytes, and liver sinusoidal endothelial cells. These interactions promote immune suppression, fibrosis, angiogenesis, and metabolic adaptation, while infiltrating immune cells such as myeloid cells, T cells, and natural killer cells are reprogrammed toward dysfunctional states that limit immunotherapy efficacy. We integrate these mechanistic insights with clinical data from cancers that frequently metastasize to the liver, highlighting consistent patterns of immunotherapy resistance and emerging combination strategies aimed at overcoming liver-specific barriers.