三阴性乳腺癌(TNBC)是最具侵袭性的乳腺癌亚型,化疗是TNBC的基础治疗。遗憾的是,新发现表明,化疗促进了肿瘤微环境的促转移改变.细胞外囊泡(EV)与癌症耐药性和转移密切相关。然而,死亡癌细胞释放的EV对TNBC预后和相应治疗策略的影响研究甚少.这项研究表明,紫杉醇化疗从凋亡的TNBC细胞(EV-Apo)中引发了富含CXCL1的EV。EV-Apo通过激活PD-L1信号使M2巨噬细胞极化来促进共培养的TNBC细胞的化学抗性和侵袭。然而,bauhuosideI(BHS)通过调节EV-Apo信号显着使共培养的TNBC细胞对紫杉醇化疗敏感。机械上,BHS显着降低了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细胞多囊体(MVB)内的腔内囊泡(ILV)的生物发生来减少EV-Apo的释放。此外,BHS与flotillin2(FLOT2)的LEU104残基结合,并中断了其与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生物发生的阻断。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(TAMs)的M2极化,使紫杉醇显着化学致敏以抑制体内TNBC转移。这项开创性的研究揭示了EV-ApoCXCL1作为化学致敏TNBC的新型治疗靶标,并提出BHS作为一种有前途的化疗佐剂,通过干扰EV-ApoCXCL1的生物发生来改善TNBC的化学敏感性和预后。
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.