Abstract 3364: Exosomes derived from tumor cells in acidic extracellular environment inhibit liver metastasis

Abstract Distant metastasis is the leading cause of cancer-related mortality in patients with solid tumor. Tumor cells tend to colonize specific target organs, exhibiting organ tropism. For instance, ∼85% of patients with metastatic uveal melanoma (UM) metastasize to sole organ liver; up to 50% of patients with colorectal carcinoma (CRC) develop liver metastasis. Liver-organotropic metastasis is the consequence of reciprocal cross talk between tumor cells and host microenvironment within the liver. Tumor microenvironment (TME), characterized by acidity and hypoxia, represents a hostile milieu that favors tumor cells over non-tumor cells which cannot adapt. Exosomes, small membranous vesicles encompassing biologically active components (namely proteins, miRNAs, and lipids, etc.), are pivotal in mediating intercellular communication. We aimed at exploring the mechanism by which exosomes mediating the intercellular communication in liver colonization. We found that hepatic metastasis in CRC was significantly facilitated by exosomes derived from tumor cells in normal extracellular environment (normal exosomes), which was, however, remarkably diminished by those derived from tumor cells in normal extracellular environment (acidic exosomes). Further study revealed that exosomes derived from tumor cells in acidic extracellular environment were enriched with the metastasis-suppressor NME1. Acidic exosomal NME1 were uptaken by adjacent tumor cells, resulting in degradation of DDR1 and CD155 via chaperone-mediated autophagy. The decreased DDR1 abolished cancer stem-like cells in UM and CRC. Decline of CD155 in tumor cells enhanced the infiltration of CD8+ T cells in metastatic colonization in liver. These results indicated a novel mechanism whereby tumor cell-derived exosomes mediating intercellular communication to regulate hepatic metastasis. Citation Format: Bei Jin, Weijia Peng, Jingxuan Pan. Exosomes derived from tumor cells in acidic extracellular environment inhibit liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3364.