Immunotherapy has emerged as a pioneering therapeutic modality, particularly within the realm of oncology, where Chimeric Antigen Receptor T-cell (CAR-T) therapy has manifested significant efficacy in the treatment of hematological malignancies. Nonetheless, the extension of immunotherapy to solid tumors poses a considerable challenge. This challenge is largely attributed to the intrinsic “cold” characteristics of certain tumors, which are defined by scant T-cell infiltration and a diminished immune response. Additionally, the impediment is exacerbated by the elusive nature of numerous targets within the tumor microenvironment, notably those deemed “undruggable” by small molecule inhibitors. This scenario underscores an acute necessity for the inception of innovative therapeutic strategies aimed at countering the resistance mechanisms underlying immune evasion in cold tumors, thereby amplifying the efficacy of cancer immunotherapy. Among the promising strategies is the deployment of Proteolysis Targeting Chimeras (PROTACs), which facilitate the targeted degradation of proteins. PROTACs present unique advantages and have become indispensable in oncology. However, they concurrently grapple with challenges such as solubility issues, permeability barriers, and the classical Hook effect. Notably, advanced delivery systems have been instrumental in surmounting these obstacles. This review commences with an analysis of the factors contributing to the suboptimal responses to immunotherapy in cold tumors. Subsequently, it delivers a thorough synthesis of immunotherapeutic concepts tailored for these tumors, clarifying the integral role of PROTACs in their management and delineating the trajectory of PROTAC technology from bench-side investigation to clinical utilization, facilitated by drug delivery systems. Ultimately, the review extrapolates the prospective future of this approach, aspiring to present novel insights that could catalyze progress in immunotherapy for the treatment of cold tumors.

中文翻译：

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肿瘤免疫治疗中的 PROTAC 递送：我们在哪里，我们要去哪里？


免疫疗法已成为一种开创性的治疗方式，尤其是在肿瘤学领域，嵌合抗原受体 T 细胞 （CAR-T） 疗法在治疗血液系统恶性肿瘤方面表现出显着疗效。尽管如此，将免疫疗法扩展到实体瘤带来了相当大的挑战。这种挑战主要归因于某些肿瘤固有的“冷”特征，其特征是 T 细胞浸润稀少和免疫反应减弱。此外，肿瘤微环境中许多靶标的难以捉摸性加剧了这一障碍，特别是那些被小分子抑制剂认为“不可成药”的靶标。这种情况强调了创新治疗策略的迫切必要性，旨在对抗寒冷肿瘤中免疫逃避的耐药机制，从而放大癌症免疫疗法的疗效。其中有前途的策略是部署蛋白水解靶向嵌合体 （PROTAC），它促进了蛋白质的靶向降解。PROTAC 具有独特的优势，已成为肿瘤学中不可或缺的药物。然而，他们同时面临着溶解度问题、渗透性障碍和经典 Hook 效应等挑战。值得注意的是，先进的交付系统在克服这些障碍方面发挥了重要作用。本综述首先分析了导致冷肿瘤对免疫治疗反应不佳的因素。 随后，它全面综合了针对这些肿瘤量身定制的免疫治疗概念，阐明了 PROTAC 在其管理中不可或缺的作用，并描绘了 PROTAC 技术在药物递送系统的帮助下从实验室研究到临床应用的轨迹。最终，本综述推断了这种方法的前瞻性未来，希望提出新的见解，以促进免疫疗法治疗寒冷肿瘤的进展。