Stimuli-Responsive Nanoadjuvant Rejuvenates Robust Immune Responses to Sensitize Cancer Immunotherapy
Ruijie Huang, Peijie Zhou, Bo Chen, Yang Zhu, Xiaoyuan Chen, Yuanzeng Min
Abstract
Despite their immense therapeutic potential, cancer immunotherapies such as immune checkpoint blockers (ICBs) benefit only a small subset of patients. Toll-like receptor agonists reverse the immunosuppressive tumor microenvironment (TME) to enhance antitumor immunity, but their systemic administration induces side effects. This work describes a TME-responsive nanotherapeutic platform for the site-specific release of drug candidates in tumors with a significant antitumor efficacy. Imidazoquinoline (IMQ)-derived liposomal nanovesicles (LN-IMQ) triggered the antitumor ability of macrophages, mobilized T-cell immunity, and promoted the secretion of antitumor cytokines, explaining the synergistic effect of LN-IMQ with ICBs. LN-IMQ monotherapy observed complete tumor regression in 6/8 of 4T1-bearing mouse, and cured mice resisted secondary tumor challenge. Besides, LN-IMQ decreased the occurrence of lung metastases, being effective against advanced metastases. On the other hand, neoantigen-based cancer vaccine has very low immune responses. Here, we also verified that LN-IMQ can serve as an ideal tumor antigen delivery vector. Cancer cells in vitro treated with chemotherapeutic drugs included multiple neoantigens and high levels of damage-associated molecular patterns, which were then successfully encapsulated in LN-IMQ to obtain a “personalized nanovaccine” with artificially amplified antigenicity and adjuvant properties. This study developed an attractive potential personalized nanovaccine for chemotherapeutic-drug-induced tumor neoantigens and immunotherapy.