三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，化疗是 TNBC 的基石治疗。遗憾的是，新发现表明化疗促进肿瘤微环境发生促转移变化。细胞外囊泡（EV）与癌症耐药性和转移密切相关。然而，垂死癌细胞释放的 EV 对 TNBC 预后的影响以及相应的治疗策略的研究却很少。这项研究表明，紫杉醇化疗可从凋亡的 TNBC 细胞 (EV-Apo) 中诱导出富含 CXCL1 的 EV。 EV-Apo 通过激活 PD-L1 信号传导极化 M2 巨噬细胞，促进共培养 TNBC 细胞的化疗耐药和侵袭。然而，保霍苷 I (BHS) 通过调节 EV-Apo 信号使共培养的 TNBC 细胞对紫杉醇化疗显着敏感。从机制上讲，BHS 显着减少了 EV-Apo 内的 C-X-C 基序趋化因子配体 1 (CXCL1) 货物，因此通过抑制 PD-L1 激活来减弱巨噬细胞 M2 极化。此外，BHS 通过减少 TNBC 细胞多囊泡体 (MVB) 内腔内囊泡 (ILV) 的生物发生来减少 EV-Apo 释放。此外，BHS 与 flotillin 2 (FLOT2) 的 LEU104 残基结合，并中断其与 RAS 癌基因家族成员 31 (RAB31) 的相互作用，导致 RAB31-FLOT2 复合物驱动的 ILV 生物合成受阻。重要的是，BHS 通过抑制 EV-ApoCXCL1 诱导的 PD-L1 激活和肿瘤相关巨噬细胞 (TAM) 的 M2 极化，使紫杉醇显着化学增敏，从而抑制 TNBC 体内转移。这项开创性研究揭示了 EV-ApoCXCL1 作为化学敏感性 TNBC 的新型治疗靶点，并提出 BHS 作为一种有前途的化疗佐剂，通过干扰 EV-ApoCXCL1 生物发生来改善 TNBC 化学敏感性和预后。© 2024 作者。 《Journal of Extracellular Vesicles》由 Wiley periodicals LLC 代表国际细胞外囊泡学会出版。

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.