Harness Nanochemical Design to Elevate STING-Based Melanoma Immunotherapy 

The proposed research will develop an innovative and clinically relevant class of nanomaterials—DNA-based “dendritic” (branched) nanostructures—as immunotherapeutics for treating melanoma. Melanoma immunotherapies, where one seeks to harness the body’s natural immune system and reprogram it to attack melanoma tumor cells, are currently ineffective in most patients. New approaches are urgently needed to improve response rates and deliver long-lasting remissions. One promising avenue lies in utilizing a cell’s natural “alarm system,” the cGAS–STING pathway. This pathway, activated when DNA binds to the cGAS enzyme, triggers a cascade of signals that stimulates both innate and adaptive immune defenses against cancer. Clinical efforts to exploit this pathway with small molecule STING agonists have not succeeded clinically because these drugs are rapidly cleared from the body, do not enter cells efficiently, and vary in potency across patient populations.

Adding to the challenge, immune activation through cGAS-STING also increases levels of a checkpoint “brake” protein PD-L1 on tumor and immune cells, which in turn dampens tumor killing and exhausts the immune system. To overcome these hurdles, we will develop a new class of programmable DNA-based nanostructures that can carry and precisely deliver orthogonally complementary therapies: DNA sequences to activate the cGAS–STING pathway and separate short DNA sequences that block the production of PD-L1 surface protein. This proposed research innovatively develops these nanostructures as molecular platforms to structure these immunotherapeutic cues and deliver them in optimized architectures to cells. Due to the modularity of our system, we propose to harness this feature to evaluate specific structural parameters that lead to effective delivery of immune-stimulating cues as well as appropriate timing of the anti-tumor-evasion cues. Our research is a paradigm shift in the way in which melanoma treatments are developed, as it harnesses advances in chemistry and nanotechnology to expand our capabilities in immunology. With our approach, we have the opportunity to develop robust and longer-lasting melanoma immunotherapies that are effective across a wide population of patients. By uniting precise immune activation with reduced “immune brake protein” expression in a single, modular platform, this research aims to produce a versatile, next-generation immunotherapy to treat patients with melanoma.