Autophagy manipulation augments programmed cell death-induced immune responses against tumor

Abstract

Malignancy remains a life-threatening challenge worldwide. Although remarkable advances have been achieved in tumor immunotherapy, the therapeutic effects are unsatisfactory due to low immunogenicity and immunosuppressive tumor microenvironment. In this work, a phenylboronic acid-modified polymeric nano-prodrug based on β-cyclodextrin (β-CD) with chemical conjugation of shikonin (SK) and chloroquine (CQ) was developed for tumor immunotherapy. The nanoparticles demonstrate high tumor-targeting and penetrating capability, and efficient cellular uptake via the complex of phenylboronic acid and sialic acid on malignant cells. Subsequently, SK induced programmed cell death and immunogenicity in tumor cells. Noticeably, the introduction of CQ terminated autophagic flux initiated by SK and strengthened efficient antigen exposure. This led to dendritic cell (DC) activation, cytotoxic T lymphocyte infiltration, reduced immunosuppression within the tumor microenvironment, and decreased primary tumor burden and pulmonary metastasis. These data suggested that our carrier is a promising strategy to augment tumor immunogenicity and therapeutic efficiency against carcinoma.