针对肿瘤依赖的代谢脆弱性是一种吸引人的肿瘤靶向治疗策略。然而，由于肿瘤细胞的代谢可塑性和异质性导致的耐药性，代谢抑制剂的应用受到限制。在这项研究中，通过空间分辨代谢组学分析发现了胆碱代谢作为一种高度活跃的代谢脆弱性，在不同类型的癌症中表现出活跃性。因此，开发了一种以胆碱修饰为策略的小分子药物结合物（SMDCs）设计方法，通过欺骗肿瘤细胞使其大量摄取胆碱修饰的化疗药物，以实现靶向癌症治疗，而非直接抑制胆碱代谢。作为概念验证，设计了胆碱修饰的SMDCs，并进行了体外和体内的药物活性研究。该策略通过高表达的胆碱转运体实现了肿瘤靶向递送药物，并通过羧酸酯酶的位点特异性释放，提高了紫杉醇的肿瘤靶向性，保留了抑制肿瘤的效果并减少了毒性。本研究扩展了靶向代谢脆弱性的策略，并为精确癌症治疗的SMDCs的开发提供了新的思路。© 2023作者。

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy. However, metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity. Herein, choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types, and a choline-modified strategy for small molecule-drug conjugates (SMDCs) design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy, instead of directly inhibiting choline metabolism. As a proof-of-concept, choline-modified SMDCs were designed, screened, and investigated for their druggability in vitro and in vivo. This strategy improved tumor targeting, preserved tumor inhibition and reduced toxicity of paclitaxel, through targeted drug delivery to tumor by highly expressed choline transporters, and site-specific release by carboxylesterase. This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.© 2023 The Author(s).