三阴性乳腺癌（TNBC）具有侵袭性高、易转移、复发多、预后差等特点。不幸的是，目前的临床治疗方法，包括手术、放疗、化疗和免疫治疗，对TNBC患者的疗效仍然有限。在这项研究中，我们发现间皮素 (MSLN) 在蛋白质水平和亚细胞位置上的异质表达，是 TNBC 嵌合抗原受体 T (CAR-T) 细胞治疗的潜在靶点，这是由肿瘤酸化引起的微环境可能是影响治疗效果的主要障碍。碱化培养或碳酸氢钠给药显着促进MSLN的膜表达，并增强MSLN-CAR-T细胞在体外和体内的杀伤效率，并且在其他MSLN高表达的癌症中也获得了相同的结果，例如胰腺和卵巢癌。此外，机制探索表明微环境碱化引起的自噬-溶酶体功能减弱抑制了MSLN的降解。因此，微环境的碱化提高了靶抗原 MSLN 的一致性和高表达，并构成了通过 MSLN-CAR-T 细胞治疗多种实体癌的常规方法。© 作者（或其雇主）2024。 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Triple-negative breast cancer (TNBC) is characterized by high invasion, prone metastasis, frequent recurrence and poor prognosis. Unfortunately, the curative effects of current clinical therapies, including surgery, radiotherapy, chemotherapy and immunotherapy, are still limited in patients with TNBC. In this study, we showed that the heterogeneous expression at the protein level and subcellular location of mesothelin (MSLN), a potential target for chimeric antigen receptor-T (CAR-T) cell therapy in TNBC, which is caused by acidification of the tumor microenvironment, may be the main obstacle to therapeutic efficacy. Alkalization culture or sodium bicarbonate administration significantly promoted the membrane expression of MSLN and enhanced the killing efficiency of MSLN-CAR-T cells both in vitro and in vivo, and the same results were also obtained in other cancers with high MSLN expression, such as pancreatic and ovarian cancers. Moreover, mechanistic exploration revealed that the attenuation of autophagy-lysosome function caused by microenvironmental alkalization inhibited the degradation of MSLN. Hence, alkalization of the microenvironment improves the consistency and high expression of the target antigen MSLN and constitutes a routine method for treating diverse solid cancers via MSLN-CAR-T cells.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.