An acid-responsive nanoagonist delivering chemotherapy-derived tumor antigens to assist cancer immunotherapy

Abstract

Immunotherapy is being actively explored for malignant tumors through various approaches, with recent success exemplified by immune checkpoint inhibitors (ICIs), which function by restoring T-cell activity to eliminate tumor cells. Some chemotherapeutic drugs synergistically improve the therapeutic effect of ICIs, leading to their combined use in clinical practice, but their immunosuppressive effect and chemotoxicity remain a clinical dilemma. In this work, the synergistic effect of chemotherapeutics with immunotherapy was delivered without the in vivo chemotherapy treatment. Specifically, we constructed a nanovaccine using chemotherapy-derived antigens, while preserving the synergistic effect of chemotherapy—such as the upregulation of neoantigens and the release of damage-associated molecular patterns—when applied along with ICIs. R848 based delivery nanoformulation, NanoR848, captures antigens through the positively charged amine group of R848, an immune agonist. This nanodrug releases R848 and antigens in the acidic environment of lysosomes within antigen-presenting cells. The use of chemotherapy-derived antigens delivers an improved anti-tumor efficacy without observable systemic chemotoxicity when combined with an ICI. The constructed nanovaccine enhances the proportion of activated dendritic cells in tumor-draining lymph nodes and upregulates tumor-infiltrating T cells while reducing the population of regulatory T cells and other immunosuppressive compartments, echoing the immunoregulatory mechanism of ICIs. Our strategy effectively preserves the immunostimulatory effects from chemotherapy without the systemic chemotoxicity and immunosuppression associated with in vivo chemotherapy treatment, thereby offering a promising approach for cancer immunotherapy.