Mesothelin-induced lysosomal biogenesis sustains neutrophil longevity to drive brain metastasis.

Soluble mesothelin (sMSLN) shed by brain metastasis cells prolongs neutrophil survival via TLR4–JAK2–STAT3, enabling tumor colonization and outgrowth in the brain.

• Why it matters: Tumor-associated neutrophil enrichment is a defining feature of brain metastases, but the mechanism sustaining TAN enrichment in the brain is undefined.
• What they did: The study shows sMSLN binds TLR4 on neutrophils to activate JAK2–STAT3, promoting lysosomal biogenesis and function, lowering reactive oxygen species and inhibiting apoptosis; neutrophil depletion or TLR4–STAT3 blockade abrogates sMSLN-induced brain metastasis progression.
• The result: Targeting mesothelin with Anetumab reduces TAN enrichment, and combining it with TLR4 inhibition synergistically suppresses lung cancer brain metastasis, supporting the sMSLN–TLR4 axis as a therapeutic target.