Cationic lipid-polymer hybrid nanoparticle drives in situ generation and lymphatic navigation of tumor antigens to prime systemic antitumor immunity

In situ vaccinations that specifically generate tumor antigens and drive the cancer-immunity cycle to kill tumor cells have emerged as a promising therapeutic strategy for cancer treatment. However, insufficiency in a series of processes involving tumor antigens, such as tumor antigen release and lymphatic transportation, hinders antitumor immunity. Here, we prepared a series of lipid-polymer hybrid nanoformulations, and optimized a cationic lipid-polymer nanoparticles (DOTAP-hNPs), comprising a hybrid of poly(ethylene glycol)-block-poly(lactic-co-glycolic acid) (PEG-b-PLGA) and the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), for efficient in situ vaccination against cancer. DOTAP-hNPs efficiently induced immunogenic cell death (ICD) of tumor cells via inhibiting the ATPase activity and consequently generate an abundance of tumor antigens in situ. And then, the DOTAP-hNPs can capture these antigens and drive their lymphatic navigation into antigen-presenting cells (APCs) in draining lymph nodes (dLNs). Thus, intratumoral administration of DOTAP-hNPs significantly promoted APC activation in dLNs and T-cell intratumoral infiltration, eliciting robust systemic antitumor immune responses and synergistically enhancing the efficacy of checkpoint blockade therapy in several tumor models (CT26, B16F10 and 4T1). Our research presents an accessible strategy to prime systemic immunity and improve personalized cancer immunotherapy.