Virus-mimicking nanoparticles potentiate in-situ cancer vaccines by reversing intratumoral DCs via stimulating cytosolic nucleic acid sensors

The major challenge for in-situ cancer vaccines is to activate the DCs within the immunosuppressive tumor to initiate tumor-specific immune responses. By contrast, oncolytic viruses can always activate intratumoral DCs to initiate virus-specific immunity to eliminate viruses which will in turn reduce the anti-tumor effect of these viruses. To bridge the two approaches, we developed virus-mimicking nanoparticles (V-mimics) through self-assembly of artificial cyclic gadolinium-based GAMP (c·Gd·GAMP, a STING agonist), double-stranded RNA analog (Poly I: C), and indocyanine green (ICG). Within the V-mimics, c·Gd·GAMP and Poly I: C can simulate the DNA and RNA produced by virus replication to reverse the inhibition of the immunosuppressive tumor microenvironment on DCs by promoting the IFN-β secreting via activating nucleic acid sensors, thereby eliciting anti-tumor immune response in a manner akin to the immune response triggered by viruses. Notably, the V-mimics significantly promoted IFN-β secretion, enhanced DC maturation, and elicited robust tumor-specific immune memory when combined with photothermal therapy. In multiple tumor models, significant tumor inhibition was observed, including a metastasis and recurrence model. Therefore, leveraging the virus-mimicking particles to simulate the mechanism of virus-initiated specific immune responses to activate the intratumoral dendritic cells may open up new strategies for in-situ cancer vaccines.