Biomineralized Ferroptosis-Inducing Nanovaccine Based on Combination of Photothermal Therapy and Checkpoint Blockade for Melanoma

Abstract Background: Until now, treatment of refractory tumors and uncontrolled metastasis has not yet achieved satisfactory therapeutic results due to the immunosuppressive tumor microenvironment. The crucial point is inadequate in vivo immune response after tumor initial cure ablation. Here, we proposed the construction of a photothermal nanovaccine based on biomineralized ovalbumin induced ferroptosis after near-infrared triggering. Fe3+ were chelated inside exogenous antigen ovalbumin by biomineralization, and photosensitizer IR820 was loaded on the outer layer by electrostatic incorporation. Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade was combined to offer incomparable opportunities for high-effcient synergistic therapy which consists of ferroptosis, photothermal therapy and cancer immunotherapy.Results: After injection treatment, Fe3+ in the vaccine consumed glutathione (GSH) in cells, affected the expression of GPX4 and initiated Fenton reaction, resulting in ferroptosis, which promoted the immunogenic cell death (ICD). After ICD initiation, released tumor endogenous antigens aroused immune cells activation together with ovalbumin. T cells were successfully recruited and infiltrated into tumor, promising the primary tumor received direct therapy and was effectively suppressed. The photothermal effect was triggered by near-infrared irradiation. Photothermal effect of nanovaccine effectively amplified mild immune response by ferroptosis. With combining with CTLA-4 checkpoint blockade, the related cytokines and other immune indicators all showed increasing levels, which had a significant inhibition effect on distal simulated metastases growth. Conclusion:Fe@OVA-IR820 nanovaccine successfully treated primary and metastatic melanoma with combination therapy. Therefore, we could propose Fe@OVA-IR820 nanovaccine combined checkpoint blockade as a potential therapeutic strategy for melanoma treatment in the future.