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

Sci Adv. 2025 Jun 27;11(26):eadr1728. doi: 10.1126/sciadv.adr1728. Epub 2025 Jun 27.

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.

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Drug Carriers* / chemistry
  • Female
  • Humans
  • Immunogenic Cell Death / drug effects
  • Immunotherapy* / methods
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Nanoparticles* / chemistry
  • Nucleotides, Cyclic / chemistry
  • RNA, Small Interfering / genetics
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Membrane Proteins
  • B7-H1 Antigen
  • RNA, Small Interfering
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Drug Carriers
  • Nucleotides, Cyclic
  • STING1 protein, human