Overcoming B16F10 Melanoma by Local Co-Delivering Chemotherapeutics and Anti-Angiogenic Agents Using Injectable Thermoresponsive Polypeptide Hydrogels

The immunosuppressive tumor microenvironment, along with the vascular barrier within B16F10 melanoma, frequently compromises the therapeutic outcomes of antitumor immunotherapy. Hydrogels, possessing three-dimensional network structures, provide a platform for localized drug delivery. Herein, we reported a thermoresponsive polypeptide hydrogel co-loaded with mitoxantrone (MTX) and the angiogenesis inhibitor nintedanib (NE), combined with immune checkpoint blockade therapy, to address these challenges. Results demonstrated that the release of MTX induced immunogenic cell death of tumor cells and released tumor-associated antigens, while the release of NE inhibited angiogenesis, promoted drug permeation and immune cell infiltration, enhanced therapeutic efficacy, and suppressed tumor proliferation and metastasis. In a melanoma-bearing mouse model, the combination of intratumoral injection of MTX/NE-loaded hydrogel with intravenous injection of anti-PD-1 elicited a strong systemic anti-tumor immune response, successfully inhibiting tumor growth and metastasis, while prolonging animal survival. Overall, this study established a hydrogel drug delivery strategy to overcome B16F10 melanoma, demonstrating strong potential in clinical cancer therapy.