2. Academic Validation
  3. Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer

  • J Immunother Cancer. 2024 Mar 1;12(3):e008054. doi: 10.1136/jitc-2023-008054.
Yun Zhou # 1 2 3,  Wenyao Zhang # 2,  Boda Wang 2,  Pei Wang 2,  Danxiu Li 4,  Tianyu Cao 2,  Dawei Zhang 5,  Hua Han 6,  Mingfeng Bai 7,  Xin Wang 8,  Xiaodi Zhao 9,  Yuanyuan Lu 9
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 2 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 3 College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
  • 4 Department of Gastroenterology, The 980th Hospital of the PLA Joint Logistics Support Force (Primary Bethune International Peace Hospital of PLA), Shijiazhuang, Hebei, China.
  • 5 Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6 Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 7 Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • 8 Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China [email protected] [email protected] [email protected].
  • 9 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 38429070 DOI: 10.1136/jitc-2023-008054
Abstract

Background: The effectiveness of immune checkpoint inhibitors in colorectal Cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study aimed to develop a mitochondria-targeted photodynamic therapy (PDT) approach to provoke host antitumor immunity of MSS-CRC and elucidate the underlying molecular mechanisms.

Methods: The role and mechanism of mitochondria-targeted PDT in inhibiting CRC progression and inducing Pyroptosis were evaluated both in vitro and in vivo. The immune effects of PDT sensitization on PD-1 blockade were also assessed in CT26 and 4T1 tumor-bearing mouse models.

Results: Here, we report that PDT using IR700DX-6T, a photosensitizer targeting the mitochondrial translocation protein, may trigger an antitumor immune response initiated by Pyroptosis in CRC. Mechanistically, IR700DX-6T-PDT produced Reactive Oxygen Species on LIGHT irradiation and promoted downstream p38 phosphorylation and active caspase3 (CASP3)-mediated cleavage of gasdermin E (GSDME), subsequently inducing Pyroptosis. Furthermore, IR700DX-6T-PDT enhanced the sensitivity of MSS-CRC cells to PD-1 blockade. Decitabine, a demethylation drug used to treat hematologic neoplasms, disrupted the abnormal methylation pattern of GSDME in tumor cells, enhanced the efficacy of IR700DX-6T-PDT, and elicited a potent antitumor immune response in combination with PD-1 blockade and IR700DX-6T-PDT.

Conclusion: Our work provides clear a understanding of immunogenic cell death triggered by mitochondria-targeted PDT, offering a new approach for enhancing the efficacy of PD-1 blockade in CRC.

Keywords

Immune Checkpoint Inhibitors; Immunotherapy; Programmed Cell Death 1 Receptor.

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