Neutrophil extracellular traps-STC1 positive feedback loop promotes immune evasion and metastasis in bladder cancer.

BACKGROUND

Immune checkpoint inhibitors (ICIs) have transformed the treatment strategy for bladder cancer (BLCA), but primary resistance still occurs in most patients. Recent evidence suggests that neutrophil extracellular traps (NETs) play a key role in cancer therapy resistance, but their specific role in BLCA remains unclear.

METHODS

An integrated analysis of multiple clinical cohorts receiving ICIs was performed to explore the link between NETs and patient outcomes. Immunofluorescence staining, in vitro co-culture system, scanning electron microscopy, and mouse lung metastasis model were used to evaluate the biological effects of NETs. Proteomics and single-cell transcriptomics analysis were further applied to elucidate the molecular mechanisms.

RESULTS

Clinically, NETs abnormally accumulated in BLCA and promoted tumor metastasis and immunotherapy resistance in mice. Mechanistically, NETs upregulated the anti-phagocytic checkpoint STC1 in tumor cells through the TLR2-MAPK-FosL1 axis. Notably, STC1 inhibited antigen presentation by sequestering calreticulin, while its secreted form enhances NET formation, forming a self-reinforcing feedback loop. In addition, secreted STC1 impaired differentiation of CD14+ precursors into mature dendritic cells, further exacerbating immune suppression.

CONCLUSION

This study revealed the critical role of the NETs-STC1 feedback loop in BLCA immunoresistance. Targeting this axis could simultaneously enhance efficacy and safety of immunotherapy, providing a novel translational strategy for overcoming resistance in clinical settings.