Breaking the Immune Sanctuary: Targeting Metastatic Niches

Metastasis is the main cause of cancer death and is driven by the systemic formation of premetastatic niches and immune sanctuaries that protect disseminated cancer cells (DCCs) from immune surveillance and therapy. This review explores the organ-specific architectural and immunologic remodeling occurring in the liver, peritoneum, and CNS, highlighting how tumor-derived factors recruit suppressive myeloid cells and drive fibrovascular changes. Advances in spatial multi-omics and compartment-specific liquid biopsies, such as cerebrospinal fluid circulating tumor DNA, are refining our ability to monitor these distinct sanctuaries. To overcome the limitations of systemic immunotherapies, which are often blunted by niche-specific immunosuppression, novel therapeutic paradigms are emerging. In this review, we highlight intratumoral delivery of type 1 conventional dendritic cells (cDC1) which effectively generates robust local and systemic CD4⁺ Th1-mediated immunity, reversing tumor microenvironment suppression and eradicating dormant DCCs. Furthermore, we detail compartment-directed strategies for the CNS sanctuary, including intrathecal immunotherapy, chimeric antigen receptor-T cells, and targeted immunocytokines. Finally, we review the clinical hurdles of targeting established sanctuaries, emphasizing the necessity of integrating systemic agents with compartment-directed, locoregional interventions like stereotactic body radiation therapy or hyperthermic intraperitoneal chemotherapy. Advancing these multimodal strategies requires adapting clinical trial designs to account for branched clonal evolution, overcoming diagnostic confounders such as immunotherapy-induced pseudoprogression, and using compartment-specific end points to accurately capture niche-directed efficacy.