Some chemotherapeutic agents, such as anthracyclines
and oxaliplatin,
can induce immunogenic cell death (ICD) with additional immune responses
against cancer. However, ICD-based immunotherapy is limited by the
nonspecific distribution of drugs and various side effects. Here,
an immunostimulatory self-assembled tetrahedral framework nucleic
acid (tFNA) vehicle was constructed to potentiate the chemo-immunotherapy,
in which doxorubicin (DOX) acted as a chemotherapeutic agent and an
ICD-inducer. Meanwhile, the immunostimulatory CpG-tFNA was employed
as a nanocarrier to deliver DOX and an adjuvant to enhance the immunotherapy.
Damage-associated molecular patterns (DAMPs) generated by DOX from
dying tumor cells, such as calreticulin (CRT), high mobility group
protein 1(HMGB1), and adenosine triphosphate (ATP), can activate dendritic
cells (DCs) and trigger an immunological response. Afterward, CpG-tFNA
with immunostimulatory properties works to boost the DOX-induced immunotherapy.
Consequently, CpG-tFNA/DOX showed excellent antitumor effects and
immunological activation, including CD8+ T cell proliferation
and antitumor cytokine TNF-α and IFN-γ secretion. Moreover,
chemo-immunotherapy can also be enhanced synergistically when coadministered
with PD-L1. In conclusion, CpG-tFNA/DOX promotes the ICD-associated
chemo-immunotherapy and strengthens the connection between traditional
chemotherapy and immunotherapy, representing a novel strategy for
clinical application. Moreover, the concept of ICD-related immunotherapy
can also be extended to other treatments such as radiotherapy which
can induce immunogenic cell death as well.