Issue

Vol. 18 (2026)

Synergistic Ferroptosis–Immunotherapy Nanoplatforms: Multidimensional Engineering for Tumor Microenvironment Remodeling and Therapeutic Optimization

https://doi.org/10.1007/s40820-025-01862-6
Xiao Wei
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Yanqiu Jiang
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Feiyang Chenwu
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Zhi Li
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Jie Wan
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Zhengxi Li
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Lele Zhang
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China
Jing Wang
Section of Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Heidelberg 69117, Germany
Mingzhu Song
School of Preclinical Medicine, Chengdu University, Chengdu 610106, People’s Republic of China

Corresponding Author: Xiao Wei

weixiao@cdu.edu.cn

Nano-Micro Letters, Vol. 18 (2026), Article Number: 56

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.


Highlights:
1 First systematic integration: This work presents the first comprehensive outline of the synergistic potential of nanoparticle-enabled ferroptosis–immunotherapy strategies against malignancies, moving beyond studies solely focusing on ferroptosis induction or standalone nanotherapeutics in cancer.
2 Multidimensional nanoplatform design: Establishes advanced design principles for functionalized nanoplatforms, including rational material selection, structural configuration, physicochemical modulation, multifunctional integration, and AI-enabled design, to overcome tumor microenvironment barriers and optimize ferroptosis–immunotherapy efficacy.
3 Translational focus & AI integration: Provides a critical analysis of translational hurdles for ferroptosis–immunotherapy nanoplatforms across preclinical and clinical development, proposing actionable solutions while pioneering the integration of artificial intelligence into future nanoplatform design and onco-immunotherapy direction.

Keywords

Ferroptosis–immunotherapy Nanoplatforms Tumor microenvironment Synergistic strategies Nanocarrier design
Wei, Xiao, Yanqiu Jiang, Feiyang Chenwu, Zhi Li, Jie Wan, Zhengxi Li, Lele Zhang, Jing Wang, and Mingzhu Song. 2025. “Synergistic Ferroptosis–Immunotherapy Nanoplatforms: Multidimensional Engineering for Tumor Microenvironment Remodeling and Therapeutic Optimization”. Nano-Micro Letters 18 (September):56. https://doi.org/10.1007/s40820-025-01862-6.
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