Tumor-targeting nanocarriers amplified immunotherapy of cold tumors by STING activation and inhibiting immune evasion

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Abstract
The low immunogenicity and immune escape are bottlenecks for effective tumor immunotherapy. Here, we synthesized multifunctional polymers comprising a photosensitizer and cationic and thiol derivates and engineered a galactose-installed stimulator of interferon genes (STING) agonist and programmed death ligand 1 (PD-L1) small interfering RNA (siPDL1)–encapsulated nanocarriers (cGAMP-siPDL1@GalNPs) for synergistic immunotherapy of low immunogenic tumors through stimulating robust immune responses. cGAMP-siPDL1@GalNPs efficiently delivered the drugs into cancer cells by targeting the galactose receptors to trigger photo-/redox-/pH-activated drug release. cGAMP-siPDL1@GalNPs stimulated robust antitumor immunity via STING activation and immunogenic cell death (ICD) and inhibited immune escape via knockdown of PD-L1 expression in tumors, which synergistically regulated the immune-suppressive tumor microenvironment. Upon laser irradiation, the nanocarriers efficiently eradicated primary melanoma and orthotopic triple-negative breast tumors and induced ICD effects, which synergically inhibited the distant tumor and spontaneous lung metastasis with improved survival rates. This study presents a strategy for developing nanocarriers to activate antitumor immunity and regulate immune invasion for effective immunotherapy.

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