Checkpoint blockade
immunotherapy is promising for clinical treatment of various malignant
tumors. However, checkpoint blockade
immunotherapy suffers from a low response rate due to insufficient
tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor-microenvironment-activatable binary cooperative
prodrug nanoparticle (
BCPN) is rationally designed to improve
immunotherapy by synergistically modulating the immune tumor microenvironment.
BCPN is purely constructed from a
tumor acidity and reduction dual-responsive
oxaliplatin (OXA)
prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction-activatable homodimer of
NLG919 for inactivating
indoleamine 2,3-dioxygenase 1, which is a key regulator for ITM. Upon
tumor-acidity-triggered cleavage of the poly(
ethylene glycol) shell, PN shows negative to positive charge switch for enhanced
tumor accumulation and deep penetration. OXA and
NLG919 are then activated in the
tumor cells via
glutathione-mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of
cancer cells. Meanwhile,
NLG919 downregulates IDO-1-mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and
NLG919 to regress
tumor growth and prevent
metastasis of mouse models of both breast and
colorectal cancer.