Abstract Background Emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic breast cancer cells induced by paclitaxel treatment were sorted and their released exosomes (exo-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in exo-dead. Zebrafish and mouse xenograft models were used to investigate the effect of exo-dead on breast cancer progression in vivo . Multiple molecular biological experiments were conducted to determine the underlying mechanisms of exo-dead in promoting breast cancer, as well as its intervention values. Results It was demonstrated that exo-dead were phagocytized by macrophages and induced breast cancer metastasis by promoting the infiltration of immunosuppressive PD-L1 + TAMs. Chemokine array identified CXCL1 as a crucial component in exo-dead to activate TAM/PD-L1 signaling. Exosomal CXCL1 knockdown or macrophage depletion significantly inhibited exo-dead-induced breast cancer growth and metastasis. Mechanistic investigations revealed that CXCL1 exo-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting exosomal CXCL1 signals to enhance paclitaxel chemosensitivity and limit breast cancer metastasis without noticeable toxicities. Conclusions Our results highlight CXCL1 exo-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve breast cancer prognosis.

Dying cell-released exosomal CXCL1 promotes breast cancer metastasis by activating TAM/PD-L1 signaling