Journal Club: Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways

Cancer Cell Volume 44, Issue 6p1160-1178.e8June 08, 2026

Highlights

• High-throughput scFCM profiling of TME linking CSCs to immunosuppression in TNBC

• CSC-derived EVs-TSPAN8⁺ interact with CD103 to activate LKB1-AMPK-FOXP3 axis in Tregs

• FOXP3 upregulates CD103 expression, a feedback loop driving CD103⁺FOXP3⁺ Treg formation

• Neutralizing EVs-TSPAN8⁺ synergizes with anti-PD-1 therapy in TNBC preclinical models

Summary

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 αEβ7) 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.