2. Academic Validation
  3. Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist

Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist

  • Adv Sci (Weinh). 2025 Jan 22:e2409835. doi: 10.1002/advs.202409835.
Guodong Li 1,  Ruoxin Du 1,  Donghui Wang 2,  Xiangmei Zhang 3,  Lizhuo Wang 4,  Shuangpeng Pu 1,  Xiaoju Li 5,  Shuning Wang 1 6,  Juliang Zhang 2,  Beichen Liu 7,  Yuan Gao 1,  Huadong Zhao 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, P. R. China.
  • 2 Department of Thyroid, Breast, and Vascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, P. R. China.
  • 3 Hebei Provincial Cancer Institute, Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, P. R. China.
  • 4 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.
  • 5 Bioinformatics Center of AMMS, Beijing, 100850, P. R. China.
  • 6 Research Institution, Xijing hospital, The Fourth Military Medical University, Xi'an, 710032, P. R. China.
  • 7 Department of Hematology, Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, P. R. China.
  • 8 Department of General Surgery, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, P. R. China.
PMID: 39840546 DOI: 10.1002/advs.202409835
Abstract

Leaky and structurally abnormal blood vessels and increased pressure in the tumor interstitium reduce the infiltration of CAR-T cells in solid tumors, including triple-negative breast Cancer (TNBC). Furthermore, high burden of tumor cells may cause reduction of infiltrating CAR-T cells and their functional exhaustion. In this study, various effector-to-target (E:T) ratio experiments are established to model the treatment using CAR-T cells in leukemia (high E:T ratio) and solid tumor (low E:T ratio). It is found that the antitumor immune response is decreased in solid tumors with low E:T ratio. Furthermore, single cell Sequencing is performed to investigate the functional exhaustion at a low ratio. It is revealed that the inhibition of mitophagy-mediated mitochondrial dysfunction diminished the antitumor efficacy of CAR-T-cell therapy. The Mitophagy agonist BC1618 is screened via AI-deep learning and cytokine detection, in vivo and in vitro studies revealed that BC1618 significantly strengthened the antitumor response of CAR-T cells via improving Mitophagy. Here, injection hydrogels are engineered for the controlled co-delivery of CAR-T cells and BC1618 that improves the treatment of TNBC. Local delivery of hydrogels creates an inflammatory and mitophagy-enhanced microenvironment at the tumor site, which stimulates the CAR-T cells proliferation, provides antitumor ability persistently, and improves the effect of treatment.

Keywords

CAR‐T‐cell therapy; TNBC; hydrogel co‐delivery; mitophagy agonist; single cell sequencing.

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