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

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.