Biomimetic mineralized nanocarriers to enhance tumor immunotherapy by remodeling cholesterol metabolism
image: The nanosystem AVA-COD@Fe disrupts cholesterol metabolism in tumor cells, thereby inhibiting their migration, promoting ferroptosis, and suppressing tumor growth and metastasis. Concurrently, the immune sensitizer avasimibe reprograms cholesterol distribution to enhance CD8⁺ T cell activity. Combined with anti-PD-L1, this approach elicits a potent systemic antitumor immune response.
Credit: Nano Research, Tsinghua University Press
A research team led by He Lian and Zhaoxu Meng from Shenyang Pharmaceutical University has developed a novel biomimetic nanosystem that cripples cancer cells by targeting their abnormal cholesterol metabolism while simultaneously activating a powerful anti-tumor immune response. This innovative strategy, which combines the nanosystem with existing immunotherapy, demonstrated a robust ability to inhibit both primary tumor growth and metastasis, highlighting a promising new avenue for cancer treatment.
Cholesterol is a crucial building block for cancer cells and is essential for their rapid growth and metastasis. The newly engineered nanosystem, named AVA-COD@Fe, is designed to deplete this vital resource within tumors.
The system operates through a coordinated two-pronged approach. First, it delivers cholesterol oxidase (COD), an enzyme that can deplete cholesterol within tumor cells. This directly impairs the ability of cancer cells to migrate and handle oxidative stress. Second, the breakdown of cholesterol produces hydrogen peroxide (H₂O₂) inside the cells. This self-generated H₂O₂ compensates for the levels in tumors, thereby significantly enhancing a form of cell death known as ferroptosis.
“The brilliance of this design lies in its ability to turn cancer's own dependency on cholesterol into a weapon against it,” said He Lian, senior author of the study. “The nanosystem not only “starves” the cancer cells but also employs an enzyme to convert cholesterol into hydrogen peroxide, a key mediator that facilitates the execution of ferroptosis.”
The therapeutic strategy does not stop there. The nanosystem also contains an immune-sensitizing drug, avasimibe, which can reconfigure the cholesterol distribution in both tumor cells and immune cells. In treated mice, this reprogramming of the tumor microenvironment, synergizing with the immunogenic cell death (ICD) induced by ferroptosis, has been proven to recruit and activate anti-cancer cytotoxic T lymphocytes in the host.
To induce a potent systemic anti-tumor response, the researchers combined their nanosystem with an anti-PD-L1 antibody. This combination therapy effectively inhibited both primary and metastatic tumors and established durable immune memory.
“This study confirms that targeting tumor cholesterol metabolism is a feasible and effective strategic approach for cancer therapy,” He Lian concluded. “We simultaneously deprive the tumor of a critical resource, trigger its self-destruction, and activate the immune system. This multi-pronged strategy holds great promise for the future of cancer treatment.”
The team plans to continue refining the nanosystem for future translational research.
Other contributors include Liyuan Guan, Zhaoxu Meng, Xiaoshu Zhang, Xihang Ren, Yanzhu Wang, Yake Qi, Luhua Liang, Luyao Wang, Linghe Zang, and Zhou Li from Shenyang Pharmaceutical University; Xiu Dong from Liaoning University of Traditional Chinese Medicine; and Zhenjun Chen and Yiping Mu from the Central Hospital Affiliated with Shenyang Medical College.
This work was supported by the National Natural Science Foundation of China (Grant No: 32571629), Natural Science Foundation of Liaoning Province (Grant No: 2024011874-JH4/4800, 2023-MS-198, 2023011989-JH3/4600), Scientific Research Projects of Liaoning Provincial Department of Education (Grant No: LJ212410163004, LJKMZ20221786), Career Development Support Program for Young and Middle-aged Teachers (Grant No: ZQN202208) of Shenyang Pharmaceutical University.
About Nano Research
Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.