Fabrication and functional validation of a hybrid biomimetic nanovaccine (HBNV) against Kit-mutant melanoma

Cancer nanovaccines hold the promise for personalization, precision, and pliability by integrating all the elements essential for effective immune stimulation. An effective immune response requires communication and interplay between antigen-presenting cells (APCs), tumor cells, and immune cells to stimulate, extend, and differentiate antigen-specific and non-specific anti-tumor immune cells. The versatility of nanomedicine can be adapted to deliver both immunoadjuvant payloads and antigens from the key players in immunity (i.e., APCs and tumor cells). The imperative for novel cancer medicine is particularly pressing for less common but more devastating KIT-mutated acral and mucosal melanomas that are resistant to small molecule c-kit and immune checkpoint inhibitors. To overcome this challenge, we successfully engineered nanotechnology-enabled hybrid biomimetic nanovaccine (HBNV) comprised of membrane proteins (antigens to activate immunity and homing/targeting ligand to tumor microenvironment (TME) and lymphoid organs) from fused cells (of APCs and tumor cells) and immunoadjuvant. These HBNVs are efficiently internalized to the target cells, assisted in the maturation of APCs via antigens and adjuvant, activated the release of anti-tumor cytokines/inhibited the release of immunosuppressive cytokine, showed a homotypic effect on TME and lymph nodes, activated the anti-tumor immune cells/downregulated the immunosuppressive immune cells, reprogram the tumor microenvironment, and showed successful anti-tumor therapeutic and prophylactic effects. Schematic illustration of the mechanism of action of the hybrid biomimetic nanovaccines (HBNVs) targeting tumor microenvironment (TME) and lymph nodes (LNs), activation of immune cells that are involved in the modulation or escalation of the immune responses for the tumor inhibition with reprogramming of TME. • KIT-mutated melanomas are largely resistant to current molecular and immune therapies. • This critical challenge may be overcome by modulating the TME and stimulating anti-tumor immune response. • Nanovaccine empowered through an interplay of APCs and tumor cells can effectively enhance immunotherapy. • The homotypic delivery of antigens and adjuvants is driven through a novel hybrid biomimetic nanovaccine. • The therapeutic and prophylactic antitumor effects were due to activated immunity and reprogrammed TME.