Leong Ka Fai, Chen Zihan, Coghi Paolo
Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, Macau SAR, China.
School of Pharmacy, Macau University of Science and Technology, Macau, Macau SAR, China.
Front Immunol. 2025 Jul 18;16:1622091. doi: 10.3389/fimmu.2025.1622091. eCollection 2025.
Immunotherapy has revolutionized cancer treatment by leveraging the body's immune system to recognize and eliminate tumor cells. While monoclonal antibodies and checkpoint inhibitors have shown dramatic clinical successes, small molecules are increasingly recognized for their potential to modulate the immune system with improved pharmacokinetics and oral bioavailability. The incorporation of fluorine atoms into small molecule structures has become a widely used strategy to enhance therapeutic efficacy. Fluorine's unique chemical properties such as high electronegativity, metabolic stability, and ability to modulate lipophilicity make fluorinated small molecules especially attractive for immunotherapeutic applications. This minireview highlights recent advances in fluorinated small molecules that target key immune pathways, including immune checkpoints, STING agonists, IDO inhibitors, and kinase pathways involved in immune regulation. We explore the chemical rationale, mechanisms of action, and therapeutic outcomes of fluorinated compounds currently in preclinical and clinical development. The discussion also addresses challenges such as immunotoxicity, resistance, and design strategies to overcome them. Together, these findings underscore the growing relevance of fluorinated small molecule immunotherapeutics in cancer treatment.
免疫疗法通过利用人体免疫系统来识别和消除肿瘤细胞，彻底改变了癌症治疗方式。虽然单克隆抗体和检查点抑制剂已在临床上取得了显著成功，但小分子因其具有改善药代动力学和口服生物利用度来调节免疫系统的潜力而日益受到认可。将氟原子引入小分子结构已成为提高治疗效果的广泛应用策略。氟的独特化学性质，如高电负性、代谢稳定性以及调节亲脂性的能力，使得氟化小分子在免疫治疗应用中特别具有吸引力。本综述重点介绍了靶向关键免疫途径的氟化小分子的最新进展，包括免疫检查点、STING激动剂、IDO抑制剂以及参与免疫调节的激酶途径。我们探讨了目前处于临床前和临床开发阶段的氟化化合物的化学原理、作用机制和治疗效果。讨论还涉及免疫毒性、耐药性等挑战以及克服这些挑战的设计策略。这些发现共同强调了氟化小分子免疫疗法在癌症治疗中日益增长的相关性。
