Synergistic Ferroptosis–Immunotherapy Nanoplatforms: Multidimensional Engineering for Tumor Microenvironment Remodeling and Therapeutic Optimization
Xiao X. Wei, Yanqiu Jiang, Feiyang Chenwu, Zhi Li, Jie Wan, Zhengxi Li, Lele Zhang, Jing Wang, Mingzhu Song
Abstract
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.