Nanoagonist‐Mediated GSDME‐Dependent Pyroptosis Remodels the Inflammatory Microenvironment for Tumor Photoimmunotherapy

Abstract

Immunotherapy, especially immune checkpoint blockade (ICB) antibody immunotherapy, has revolutionized the treatment ways of cancers and provided remarkable clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors with an immune-excluded or immune-suppressed phenotype is dismal due to the lack or paucity of immune infiltration in the tumor microenvironment. Herein, an emerging photoimmunotherapy based on remodeling the inflammatory microenvironment is reported, ascribed to nanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis and providing positive feedback to activate anti-PD-1 immunotherapy. An iridiumbased photosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP) lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the light activation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 to induce anti-tumor photoimmunotherapy. The pro-inflammatory factors released by pyroptotic cells remodel the inflammatory microenvironment and recruit immune cells to kill tumor cells, resulting in CD8 + cytotoxic T lymphocytes activation, PD-1 expression enhancement, and dendritic cell slightly maturation. Collectively, these findings present a synergistic strategy of photoimmunotherapy, that is, turning immunological cold tumors into hot tumors that can respond to anti-PD-1-based immunotherapy via precise pathway regulation.

Photon-Controlled Pyroptosis Activation (PhotoPyro): An Emerging Trigger for Antitumor Immune Response

“…Photoirradiation led to pyroptosis, which was found to work in concert with an anti-PD-1 agent to promote an antitumor photoimmunotherapeutic effect. 113 In this system, the IrP PS produces ROS and activates caspase-3 upon photoillumination, while the RG108 moiety gives rise to an increase in GSDME levels thus producing a chemotherapeutic (CT) effect. TME-responsive nanoparticles typically rely on tumorspecific characteristics, such as acidic and hypoxic microenvironments and overexpressed biological molecules.…”

“…(d) Schematic representation of a synergistic PDT/CT pyroptosis-inducing system based on an Ir­(III) complex-containing nanoagonist R@IrP . Adapted with permission from ref . Copyright 2022 Wiley-VCH GmbH.…”

“…Success along these lines was demonstrated by Zheng and colleagues who produced an iridium-based photosensitizer (IrP) that included the methyltransferase inhibitor RG108 ( R@IrP ; Figure d). Photoirradiation led to pyroptosis, which was found to work in concert with an anti-PD-1 agent to promote an antitumor photoimmunotherapeutic effect . In this system, the IrP PS produces ROS and activates caspase-3 upon photoillumination, while the RG108 moiety gives rise to an increase in GSDME levels thus producing a chemotherapeutic (CT) effect.…”

Recent Development of Rhenium-Based Materials in the Application of Diagnosis and Tumor Therapy

“…Cancer detection has become more sensitive and accurate. In the treatment of cancer, radiotherapy (RT) [ 25 , 26 ], chemotherapy [ 27 , 28 , 29 , 30 ], photodynamic therapy (PDT) [ 31 , 32 , 33 , 34 , 35 , 36 ], photothermal therapy (PTT) [ 37 , 38 , 39 ], sonodynamic therapy (SDT) [ 40 , 41 , 42 ], immunotherapy [ 43 , 44 , 45 ], starvation therapy (ST) [ 33 , 46 , 47 ], magnetothermal therapy (MHT) [ 48 , 49 ], and other therapies have also shown good anticancer effects. As a remarkable diagnostics reagent candidate, the Re element has attracted the attention of many researchers because of its unique physical and chemical properties.…”

Biomimetic Nanophotosensitizer Amplifies Immunogenic Pyroptosis and Triggers Synergistic Cancer Therapy

“…Photosensitizers, which generate reactive oxygen species (ROS) exposed to laser irradiation, are potential candidates to activate the caspase-3/GSDME signaling pathway and trigger pyroptosis through damaging mitochondria. [16,17] In addition, its photoactivated properties can induce spatiotemporal controllable tumor-specific pyroptosis and avoid undesired inflammatory responses. [18] While the keys to triggering efficient caspase3/GSDME-mediated pyroptosis based on generated ROS are the tumor enrichment efficiency of photosensitizers and the development of strategies to overcome intrinsic antioxidant factors in tumor cells.…”