Targeting immune heterogeneity in liver metastases through in vivo genetic engineering

The liver is both a central metabolic organ and a uniquely tolerogenic immune niche, which makes it a frequent site of liver metastases (LMS) and a challenging environment for immunotherapy. It is increasingly appreciated that resident liver cells- Kupffer cells, Ito cells, liver sinusoidal endothelial cells - as well as infiltrating myeloid and lymphoid populations, collectively establish an immunosuppressive microenvironment that favors metastatic seeding and progression. Advances in our understanding of these cell-cell interactions and the exclusion of effector T cells, have highlighted new therapeutic entry points. In parallel, innovations in gene-delivery platforms, from lentiviral and AAV vectors to lipid nanoparticles, and in engineered immune cells such as CAR-T and CAR-NK cells, are opening avenues to modulate the hepatic tumor niche. Here we review how these insights into liver immunobiology inform the design of next-generation immunotherapies for LMS, emphasizing opportunities and challenges in translating them to the clinic.