Stimuli-Responsive Nanoadjuvant Rejuvenates Robust Immune Responses to Sensitize Cancer Immunotherapy

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.