TY  - JOUR
T1  - STC1–Neutrophil Extracellular Trap Positive Feedback Loop Drives Immune Escape and Metastasis in Bladder Cancer
A1  - Sarah Louise Bennett
A1  - Claire Marie Thompson
JF  - Archive of International Journal of Cancer and Allied Science
JO  - Arch Int J Cancer Allied Sci
SN  - 3108-4834
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/89R10Bxc2B
SP  - 150
EP  - 169
N2  - Despite the clinical success of immune checkpoint inhibitors (ICIs) in bladder cancer (BLCA), many patients fail to respond due to primary resistance. Neutrophil extracellular traps (NETs) have recently emerged as critical mediators of tumor therapy resistance, yet their precise function in BLCA is still unclear. We combined data from multiple ICI-treated patient cohorts to investigate the association between NET levels and clinical outcomes. Experimental approaches—including immunofluorescence, in vitro co-culture, scanning electron microscopy, and a mouse lung metastasis model—were employed to examine NETs’ biological impact. Molecular mechanisms were further explored using proteomic profiling and single-cell transcriptomics.

BLCA samples exhibited abnormal NET accumulation, which enhanced metastasis and reduced ICI effectiveness in mice. Mechanistic studies demonstrated that NETs stimulate STC1 expression in tumor cells through the TLR2-MAPK-FosL1 pathway. STC1 restrained antigen presentation by capturing calreticulin, while its secreted form promoted further NET formation, creating a self-amplifying feedback loop. Additionally, secreted STC1 hindered CD14+ precursors from differentiating into mature dendritic cells, intensifying immunosuppression. These findings reveal a key immunosuppressive NETs-STC1 circuit in BLCA, suggesting that targeting this pathway could improve both therapeutic efficacy and safety of ICIs.
UR  - https://smerpub.com/article/stc1neutrophil-extracellular-trap-positive-feedback-loop-drives-immune-escape-and-metastasis-in-bla-oqfja4syjf4cnys
ER  -