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

• Published in: Journal for immunotherapy of cancer 2024-03, Vol.12 (3), p.e008054
• Main Authors: Zhou, Yun, Zhang, Wenyao, Wang, Boda, Wang, Pei, Li, Danxiu, Cao, Tianyu, Zhang, Dawei, Han, Hua, Bai, Mingfeng, Wang, Xin, Zhao, Xiaodi, Lu, Yuanyuan
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Apoptosis; Basic Tumor Immunology; Breast cancer; Cancer therapies; Cell adhesion & migration; Cell culture; Cell death; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - therapy; Dehydrogenases; Flow cytometry; Gasdermins - drug effects; Gasdermins - metabolism; Immune Checkpoint Inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Light; Mice; Mitochondria; Mitochondria - metabolism; Photochemotherapy; Photodynamic therapy; Programmed Cell Death 1 Receptor; Programmed Cell Death 1 Receptor - metabolism; Proteins; Pyroptosis; Reactive oxygen species; Reagents; Tumors
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2023-008054

BackgroundThe 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.MethodsThe 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.ResultsHere, 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.ConclusionOur 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.