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  3. Self-Oxygenated Hydrogel Enhances Immune Cell Response and Infiltration Via Triggering Dual DNA Damage to Activate cGAS-STING and Inhibiting CAFs

Self-Oxygenated Hydrogel Enhances Immune Cell Response and Infiltration Via Triggering Dual DNA Damage to Activate cGAS-STING and Inhibiting CAFs

  • Small. 2024 Jul 25:e2403428. doi: 10.1002/smll.202403428.
Huiting Tian 1,  Nan Zhu 2,  Haiting Wang 1,  Yanpo Li 1,  Qiuping Yang 1,  Haolin Chen 1,  Zhongming Zhou 1,  Jianhui Tan 1,  Huihui Zheng 1,  Jiayi Xie 1,  Wei Li 3,  Min Liang 4,  Zhaoze Guo 2,  Zhiyang Li 1
Affiliations

Affiliations

  • 1 Department of Thyroid, Breast and Hernia Surgery, General Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, 515000, China.
  • 2 The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Breast and Thyroid Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hunan, 421008, China.
  • 4 Department of Oncology, Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
PMID: 39051518 DOI: 10.1002/smll.202403428
Abstract

Immune Checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast Cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of Reactive Oxygen Species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H2O2 to O2, reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses.

Keywords

CAFs; DNA damage; PDT; cGAS/sting; immune response; self‐oxygenating hydrogel.

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