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.