Abstract
Regulation of stimulator of interferon genes (STING) pathway using agonists can boost antitumor immunity for cancer treatment, while the rapid plasma clearance, limited membrane permeability, and inefficient cytosolic transport of STING agonists greatly compromise their therapeutic efficacy. In this study, we describe an extracellular matrix (ECM)-degrading nanoagonist (dNAc) with second near-infrared (NIR-II) light controlled activation of intracellular STING pathway for mild photothermal-augmented chemodynamic-immunotherapy of breast cancer. The dNAc consists of a thermal-responsive liposome inside loading with ferrous sulfide (FeS2) nanoparticles as both NIR-II photothermal converters and Fenton catalysts, 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) as the STING agonist, and an ECM-degrading enzyme (bromelain) on the liposome surface. Mild heat generated by dNAc upon NIR-II photoirradiation improves Fenton reaction efficacy to kill tumor cells and cause immunogenic cell death (ICD). Meanwhile, the generated heat triggers a controlled release of cGAMP from thermal-responsive liposomes to active STING pathway. The mild photothermal activation of STING pathway combined with ICD promotes anti-tumor immune responses, which leads to improved infiltration of effector T cells into tumor tissues after bromelain-mediated ECM degradation. As a result, after treatment with dNAc upon NIR-II photoactivation, both primary and distant tumors in a murine mouse model are inhibited and the liver and lung metastasis are effectively suppressed. This work presents a photoactivatable system for STING pathway and combinational immunotherapy with improved therapeutic outcome.Graphical
Highlights
Immunotherapy can eliminate local and disseminated metastatic tumors through stimulating the host’s antitumor immune responses, and establish an effective immune memory to avoid tumor recurrence [1,2,3]
We report the synthesis of an extracellular matrix (ECM)-degrading nanoagonist with NIRII light controlled activation of intracellular stimulator of interferon genes (STING) pathway for mild Photothermal therapy (PTT)-augmented chemodynamic therapy (CDT)-immunotherapy
Materials Sulfur powder, bovine serum albumin (BSA), 1-dodecanethiol, hydrogen peroxide (H2O2), iron dichloride, and oleylamine were purchased from Aladdin (Shanghai, China). cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) was purchased from MedChemExpress (USA)
Summary
Immunotherapy can eliminate local and disseminated metastatic tumors through stimulating the host’s antitumor immune responses, and establish an effective immune memory to avoid tumor recurrence [1,2,3]. Immune checkpoint blockade therapy that uses immune checkpoint inhibitors to reverse inhibitory pathways between immune effector cells and tumor cells has been approved for the treatment of several types of cancer [4,5,6]. This therapeutic strategy is often inoperative for clinic patients [7]. CDNs that can bind with STING dimers have been used as therapeutic agonists to trigger antitumor immunity for cancer treatment [19,20,21]. The therapeutic efficacy of CDNs is often limited because of their rapid plasma clearance, poor cell membrane permeability, and inefficient transport into cytosol [22, 23]
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