Targeted tumor cell-intrinsic CTRP6 biomimetic codelivery synergistically amplifies ferroptosis and immune activation to boost anti-PD-L1 immunotherapy efficacy in lung cancer

  • J Nanobiotechnology. 2025 Jun 2;23(1):409. doi: 10.1186/s12951-025-03428-5.
Songhua Cai  #  1 ,  Jing Huang  #  1 ,  Hongjie Fan  #  2 ,  Zhilin Sui  1 ,  Chujian Huang  1 ,  Youjun Deng  1 ,  Ran Jia  1 ,  Lixu Wang  1 ,  Kai Ma  1 ,  Xiaotong Guo  1 ,  Jie He  3  4 ,  Baihua Zhang  5 ,  Zhentao Yu  6
Affiliations
  • 1. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.
  • 2. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China. [email protected].
  • 4. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. [email protected].
  • 5. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China. [email protected].
  • 6. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China. [email protected].
  • # Contributed equally.
PMID: 40457410 DOI: 10.1186/s12951-025-03428-5
Abstract

Background: Lung adenocarcinoma (LUAD) is a refractory tumor with high incidence, high mortality, and easy development of drug resistance. Represented by PD-L1, the rise of immunotherapy and multidrug combinations offers a reliable approach to treating LUAD. However, there are still some patients with immunoresistance or insensitivity, and new combination therapies are still needed.

Methods: In this study, cyclic arginine-glycine-aspartate (cRGD)/erythrocyte membrane (RBCM) double-head nanocarriers were designed. This nanocarrier platform targets CTRP6 in tumors and delivers gemcitabine to block the progression of lung Cancer. PD-L1 monoclonal antibodies were used as a codelivery platform to explore the effect of the codelivery platform on immunotherapy.

Results: CTRP6 expression was negatively correlated with the prognosis of patients with lung adenocarcinoma. The codelivery platform @RBCM/cRGD-PhLips effectively targeted tumor cells. Co-carrying gemcitabine and targeting CTRP6 expression, it amplified Ferroptosis of tumor cells through the NRF2/STAT3 signaling pathway, activated intratumoral immunity, and promoted M1-like macrophage transformation and CD8+ T-cell recruitment. This platform amplified the immune effect of PD-L1 monoclonal antibodies to play an anti-lung Cancer role.

Conclusions: The synergistic delivery of the targeted tumor cell-intrinsic CTRP6 biomimetic nanocarrier provides a new approach to the combined immunotherapy of lung Cancer.

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