Exosomal misfolded α1-antitrypsin triggers a cytosolic GRP78-dependent unfolded protein response and pro-survival signaling in pre-metastatic tissues.

Tumor-derived exosomes (TDEs) promote cancer progression by transmitting oncogenic signals to adjacent cells. However, their impact on distant, non-malignant tissues remains poorly defined, particularly with respect to their bioactive cargo. Subsequently, a misfolded form of α1-antitrypsin (mA1AT) was identified as an exosomal component secreted by 4T1 mice mammary tumor cells, and validated in breast cancer patient serum. Exosome-mediated delivery of mA1AT to healthy lung, liver and bone marrow cells, prospective sites for metastasis, induces cytoplasmic expression of GRP78, triggers a pro-survival unfolded protein response (UPR), activates proliferation and inflammation, while suppressing apoptosis, both in vitro and in vivo. In silico modeling and co-immunoprecipitation confirm interaction between GRP78 and mA1AT, implicating non-canonical UPR activation. Depletion of mA1AT from exosomes reduces these effects, signifying its role in exosome-mediated transfer of oncogenic traits to distant, non-malignant tissues, and highlighting its potential as a therapeutic target to limit systemic dissemination of tumorigenic cues.