Wei Xiao, Jiang Yanqiu, Chenwu Feiyang, Li Zhi, Wan Jie, Li Zhengxi, Zhang Lele, Wang Jing, Song Mingzhu
School of Preclinical Medicine, Chengdu University, Chengdu, 610106, People's Republic of China.
Section of Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, 69117, Germany.
Nanomicro Lett. 2025 Sep 2;18(1):56. doi: 10.1007/s40820-025-01862-6.
Emerging ferroptosis-immunotherapy strategies, integrating functionalized nanoplatforms with ferroptosis-inducing agents and immunomodulatory therapeutics, demonstrate significant potential in managing primary, recurrent, and metastatic malignancies. Mechanistically, ferroptosis induction not only directly eliminates tumor cells but also promotes immunogenic cell death (ICD), eliciting damage-associated molecular patterns (DAMPs) release to activate partial antitumor immunity. However, standalone ferroptosis therapy fails to initiate robust systemic antitumor immune responses due to inherent limitations: low tumor immunogenicity, immunosuppressive microenvironment constraints, and tumor microenvironment (TME)-associated physiological barriers (e.g., hypoxia, dense extracellular matrix). To address these challenges, synergistic approaches have been developed to enhance immune cell infiltration and reestablish immunosurveillance, encompassing (1) direct amplification of antitumor immunity, (2) disruption of immunosuppressive tumor niches, and (3) biophysical hallmark remodeling in TME. Rational nanocarrier design has emerged as a critical enabler for overcoming biological delivery barriers and optimizing therapeutic efficacy. Unlike prior studies solely addressing ferroptosis or nanotechnology in tumor therapy, this work first systematically outlines the synergistic potential of nanoparticles in combined ferroptosis-immunotherapy strategies. It advances multidimensional nanoplatform design principles for material selection, structural configuration, physicochemical modulation, multifunctional integration, and artificial intelligence-enabled design, providing a scientific basis for efficacy optimization. Moreover, it examines translational challenges of ferroptosis-immunotherapy nanoplatforms across preclinical and clinical stages, proposing actionable solutions while envisioning future onco-immunotherapy directions. Collectively, it provides systematic insights into advanced nanomaterial design principles and therapeutic optimization strategies, offering a roadmap for accelerating clinical translation in onco-immunotherapy research.
新兴的铁死亡免疫治疗策略，即将功能化纳米平台与铁死亡诱导剂和免疫调节疗法相结合，在治疗原发性、复发性和转移性恶性肿瘤方面显示出巨大潜力。从机制上讲，诱导铁死亡不仅能直接消除肿瘤细胞，还能促进免疫原性细胞死亡（ICD），引发损伤相关分子模式（DAMP）释放，从而激活部分抗肿瘤免疫。然而，由于存在固有局限性，单独的铁死亡疗法无法引发强大的全身抗肿瘤免疫反应，这些局限性包括：肿瘤免疫原性低、免疫抑制微环境限制以及肿瘤微环境（TME）相关的生理屏障（如缺氧、致密的细胞外基质）。为应对这些挑战，已开发出协同方法来增强免疫细胞浸润并重新建立免疫监视，包括（1）直接增强抗肿瘤免疫力，（2）破坏免疫抑制性肿瘤微环境，以及（3）重塑TME中的生物物理特征。合理的纳米载体设计已成为克服生物递送障碍和优化治疗效果的关键因素。与以往仅关注肿瘤治疗中的铁死亡或纳米技术的研究不同，这项工作首次系统地概述了纳米颗粒在联合铁死亡免疫治疗策略中的协同潜力。它提出了用于材料选择、结构配置、物理化学调节、多功能整合以及人工智能辅助设计的多维纳米平台设计原则，为疗效优化提供了科学依据。此外，它还研究了铁死亡免疫治疗纳米平台在临床前和临床阶段的转化挑战，提出了可行的解决方案，同时展望了未来肿瘤免疫治疗的方向。总体而言，它提供了对先进纳米材料设计原则和治疗优化策略的系统见解，为加速肿瘤免疫治疗研究的临床转化提供了路线图。
