RAB7A-enriched extracellular vesicles drive early-metastasis and immune evasion in triple-negative breast cancer.

Early-metastatic triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and responds poorly to immunotherapy. However, mechanisms of metastasis or immune evasion remain incompletely understood. This study demonstrates that tumor-derived small extracellular vesicles (sEV) from a clinical cohort of 16 TNBC patients promote cytoskeletal remodeling, tumor growth, and lung metastasis. Label-free quantitative proteomic analysis revealed that RAB7A is enriched in sEVs from early-metastatic patients, whereas other endolysosomal proteins were not markedly altered. Mechanistically, sEV-delivered RAB7A activated the MAPK/ERK signaling pathway, thereby promoting paxillin phosphorylation, F-actin polymerization, and enhanced cell motility. Concurrently, RAB7A upregulated c-MYC expression which bound to the CD274 promoter and increased PD-L1 expression, contributing to immune evasion. Importantly, combined treatment with the RAB7A inhibitor CID1067700 and anti-PD-1 suppressed both tumor growth and metastasis, and enhanced intratumoral infiltration of CD8⁺ T cell. Collectively, this study found that the sEV/RAB7A/ERK axis promotes early metastasis and immune evasion in TNBC, and propose that targeting RAB7A-enriched sEV plus PD-1 blockade represents a mechanistically rational therapeutic strategy in aggressive TNBC.