Hsa-derived supramolecular nanomedicine loaded with demethylzeylasteral potentiates antitumor immunity in melanoma by restraining mitochondrial function and activating cGAS-STING pathway

Schematic illustration of the construction and mechanism of HSA-T96. HSA-T96 was constructed by the supramolecular self-assembly between T96 and the partially reductive HSA. HSA-T96 accumulated specifically in tumor sites and internalized in melanoma cells by enhanced permeability and retention (EPR) effect. In a spontaneous and controllable way, T96 was released in the intracellular reductive environment, which subsequently induced tumor cell death and activated the immunostimulatory mtDNA-cGAS-STING signaling. This figure was produced by Figdraw. • A biomimetic nanomedicine (HSA-T96) was developed via supramolecular self-assembly between the partially reductive HSA and T-96. • HSA-T96 exhibited considerable tumor suppression effect with a remarkable tumor-targeting ability and safety profile in vivo . • HSA-T96 potently reprogrammed melanoma tumor microenvironment from a “cold” to a “hot” state, with prominently increased infiltration and activation of CD8 + T cells. • HSA-T96 significantly restrained mitochondria function, which led to mtDNA leakage, activation of cGAS-STING pathway, and subsequent chemokines and cytokines secretion. Melanoma presents a formidable therapeutic challenge due to its aggressive nature and frequent resistance to targeted therapy and immunotherapy. Although the natural triterpene Demethylzeylasteral (T-96) possesses antitumor activity, its poor solubility and systemic toxicity limit its clinical translation. To overcome these barriers, we developed a biomimetic nanomedicine (HSA-T96) via supramolecular self-assembly of T-96 with partially reductive human serum albumin (HSA). As expected, HSA-T96 significantly suppressed tumor growth, exhibiting a remarkable targeting and safety profile. Crucially, HSA-T96 remodeled the tumor immune microenvironment especially by promoting the infiltration and activation of cytotoxic CD8 + T cells. Mechanistically, transcriptomic analysis and functional studies revealed that HSA-T96 prominently suppressed mitochondrial function and induced the leakage of oxidized mitochondrial DNA (mtDNA) into the cytosol. In addition, this mtDNA activated the cGAS-STING pathway, triggering the production of proinflammatory chemokines and cytokines that are responsible for potentiated antitumor immunity. Consequently, HSA-T96 potently increased the efficacy of anti-PD-1 immunotherapy in the B16F10 xenograft mouse model. Taken together, HSA-T96, as a versatile nanoplatform, not only improves the targeting and safety profile of T-96 but also activates immunostimulatory function via the mtDNA-cGAS-STING axis, offering a promising combinatorial strategy for melanoma immunotherapy.