Synthetic immunogenic cell death mediated by intracellular delivery of STING agonist nanoshells enhances anti-cancer chemo-immunotherapy.

Many favorable anti-cancer treatments owe their success to the induction immunogenic cell death (ICD) in cancer cells, which activates antigen presenting cells to prime anti-cancer adaptive immunity. We describe a strategy to synthetically induce ICD by delivering the agonist of stimulator of interferon genes (STING), 2’3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) into tumor cells using hollow polymeric nanoshells. Following intracellular delivery of exogenous adjuvant, subsequent cytotoxic treatment creates immunogenic cellular debris, by a process herein termed synthetic immunogenic cell death (sICD). sICD is indiscriminate to the type of chemotherapeutics adopted for cancer treatment and enables co-localization of exogenously administered immunologic adjuvants and tumor antigens for enhanced antigen presentation and development of anticancer adaptive immunity. In three mouse tumor models with distinctive chemotherapeutic treatments, sICD enhances therapeutic efficacy and restrains tumor progression. The present study highlights the therapeutic benefit of temporally coordinated STING agonists delivery to cancer cells, paving ways to new nanoparticle designs for enhancing anti-cancer chemo-immunotherapies.