A Mitochondrion‐Targeted NIR‐II Modulator for Synergistic Ferroptosis–Immunotherapy
Immune checkpoint inhibitors (ICIs) have limited clinical efficacy against gastric cancer (GC) due to the nonimmunogenic tumor microenvironment. Therefore, inducing immunogenic cell death (ICD) to reprogram the immunogenic landscape is essential. This study develops HD-FA nanoparticles by encapsulating a novel mitochondrion-targeted NIR-II modulator, HD, within DSPE-PEG-FA. HD-FA exhibits superior spatiotemporal resolution, robust tumor accumulation, and minimal adverse effects. Upon 808 nm laser irradiation, HD-FA generates reactive oxygen species, leading to ferroptosis and oxidative stress damage in GC cells by inhibiting the SLC7A11/GSH/GPX4 axis. HD-FA triggers ICD, resulting in antitumor activity not only in primary tumors but also in distant tumors. Moreover, HD-FA promotes dendritic cell maturation, increases the effector-memory T-cell frequency, and reduces the presence of myeloid-derived suppressor cells, thereby fostering enhanced antitumor immunity. This study presents the first report of a novel NIR-II modulator for GC immunogenic synergistic therapy with ICIs, marking significant advancements in the fight against GC.
Authors
- Jialu Gao
- Wuyue Su (ORCID: https://orcid.org/0000-0002-4347-1502)
- Xiaodong Zeng (ORCID: https://orcid.org/0000-0002-1442-0538)
- Dan Fu (ORCID: https://orcid.org/0000-0001-9243-8306)
- Miao Wang (ORCID: https://orcid.org/0000-0003-3065-0197)
- Yongchang Wei (ORCID: https://orcid.org/0000-0001-7205-4663)
- Xiaofen Wang (ORCID: https://orcid.org/0000-0003-3543-1073)
- Qihang Ding (ORCID: https://orcid.org/0000-0002-2665-9036)
- Runping Yang
- Guopeng Chen (ORCID: https://orcid.org/0000-0002-0297-3952)
- Yuling Xiao (ORCID: https://orcid.org/0000-0003-1237-941X)
- Xuechuan Hong (ORCID: https://orcid.org/0000-0001-6834-3278)
- Tianhe Huang (ORCID: https://orcid.org/0000-0002-2737-4016)
- Nan Zhang (ORCID: https://orcid.org/0000-0002-5877-1786)
- Pan Liu (ORCID: https://orcid.org/0009-0001-6305-6429)
- Qian Wang (ORCID: https://orcid.org/0000-0003-4755-7001)
- Min Luo (ORCID: https://orcid.org/0000-0002-5276-9327)
Institutions
- Korea University (KR)
- Chinese Academy of Sciences (CN)
- Chinese PLA General Hospital (CN)
- Wuhan University (CN)
- Shanghai Institute of Materia Medica (CN)
- Zhongnan Hospital of Wuhan University (CN)
Publication Details
- Journal
- Small
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1002/smll.202501397
- Citations
- 5
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 7.59
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province