Self-immolated Nanoadjuvant for In-Situ Vaccination Immunotherapy of Colorectal Cancer.

Vaccination immunotherapy has revolutionized cancer treatment modalities. Although the immunomodulatory adjuvant generally employs for potentiating vaccine response, systemic administration may drive immune-related side effects, even immune tolerance. Therefore, tunable immunoadjuvants are highly desirable to simultaneously stimulate the immune response and mitigate systemic toxicity. We herein reported self-immolated nanoadjuvants to potentiate vaccination immunotherapy of cancer. The nanoadjuvants were engineered by co-assembling an intracellular acidity-ionizable polymeric agonist of toll-like receptor 7/8 resiquimod (R848) and polymeric photosensitizer pyropheophorbide a (PPa). The resultant nanoadjuvants specifically accumulated at the tumor site via passive targeting and were dissociated in the acidic endosome versicles to activate PPa via protonation of the polymer backbone. Upon 671 nm laser irradiation, PPa performed photodynamic therapy to induce immunogenic cell death of tumor cells and subsequently released R848 in a customized manner, which synergistically activated dendritic cells, promoted antigen cross-presentation, and eventually recruited cytotoxic T lymphocytes for tumor regression. Furthermore, the synergistic in-situ vaccination immunotherapy with immune checkpoint blockade induced sustained immunological memory to suppress tumor recurrence in the rechallenged colorectal tumor model. This article is protected by copyright. All rights reserved.