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Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

ABSTRACT: Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono-activatable semiconducting polymer nanoreshapers (SPN_DN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPN_DN H contain a semiconducting polymer, hydrogen sulfide (H₂ S) donor, and indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919), which are encapsulated by singlet oxygen (¹ O₂ )-responsive shells with modification of hyaluronidase (HAase). After accumulation in orthotopic pancreatic tumor sites, SPN_DN H degrade the major content of tumor microenvironment hyaluronic acid to promote nanoparticle enrichment and immune cell infiltration, and also release H₂ S to relieve tumor hypoxia via inhibiting mitochondrion functions. Moreover, the relieved hypoxia enables amplified sonodynamic therapy (SDT) under ultrasound (US) irradiation with generation of ¹ O₂ , which leads to immunogenic cell death (ICD) and destruction of ¹ O₂ -responsive components to realize sono-activatable NLG919 release for reversing IDO-based immunosuppression. Through such a multiple remodeling mechanism, a potent antitumor immunological effect is triggered after SPN_DN H-based treatment. Therefore, the growths of orthotopic pancreatic tumors in mouse models are almost inhibited and tumor metastases are effectively restricted. This study offers a sono-activatable nanoplatform to multiply remodel tumor microenvironment for effective and precise immunotherapy of deep-tissue orthotopic tumors.

SUBMITTER: Li M

PROVIDER: S-EPMC10724419 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

Li Meng M Liu Yue Y Zhang Yijing Y Yu Ningyue N Li Jingchao J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20231023 35

Due to the complicated tumor microenvironment that compromises the efficacies of various therapies, the effective treatment of pancreatic cancer remains a big challenge. Sono-activatable semiconducting polymer nanoreshapers (SPNDN H) are constructed to multiply remodel tumor microenvironment of orthotopic pancreatic cancer for potent immunotherapy. SPNDN H contain a semiconducting polymer, hydrogen sulfide (H2 S) donor, and indoleamine 2,3-dioxygenase (IDO) inhib ...[more]

PMID: 37870196

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Project description:Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-x Se nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Dataset Information

Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

Publications

Sono-Activatable Semiconducting Polymer Nanoreshapers Multiply Remodel Tumor Microenvironment for Potent Immunotherapy of Orthotopic Pancreatic Cancer.

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