Cancer nanovaccine plus doxorubicin and immune checkpoint blockade overcomes chemoresistance and delays postsurgical recurrence

Abstract

Chemotherapy for solid tumors has serious limitations due to acquired chemoresistance and frequent postsurgical recurrence. In this study, we developed a chemo-immunotherapy regimen combining a chemotherapeutic agent, a dendritic cell (DC)-activating cancer nanovaccine, and immune checkpoint blockade (ICB) to overcome chemoresistance and improve long-term tumor control. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles co-encapsulating a tumor-specific antigen (HPV E7 peptide) and an adjuvant (poly I:C), termed PLGA (E7 + poly I:C)-NPs, were engineered as the nanovaccine platform. PLGA (E7 + poly I:C)-NPs promoted DC maturation and induced pro-inflammatory cytokine production. In a doxorubicin (DOX)-resistant tumor model, co-administration of PLGA (E7 + poly I:C)-NPs, DOX, and anti-PD-L1 antibody significantly reduced tumor burden, decreased tumor cell proliferation, and lowered microvessel density. This combination therapy also synergistically enhanced cytotoxic CD8⁺ T cell responses in both the spleen and tumor and delayed postsurgical recurrence, consistent with an increased effector memory T cell population. Moreover, MDR1 (ABCB1) expression was downregulated and the CD44⁺CD133⁺ cancer stem-like cell fraction was reduced, supporting reversal of chemoresistant features. Collectively, these findings demonstrate that integrating a cancer nanovaccine with chemotherapy and PD-L1 blockade can enhance antitumor immunity, overcome chemoresistance, and delay recurrence in chemoresistant tumors. This approach offers the potential to improve therapeutic outcomes and prolong survival in patients with various chemoresistant tumors.