Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways
Menée à l'aide de modèles précliniques et à partir de l'analyse protéomique d'échantillons tumoraux issus de patientes atteintes d'un cancer du sein triple négatif, cette étude met en évidence un mécanisme par lequel les cellules souches cancéreuses organisent l'échappement immunitaire via des voies de signalisation non canoniques induites par des vésicules extracellulaires
Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αE?7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.
Cancer Cell , résumé, 2026