Biomimetic Hydrogel‐Mediated Mechano‐Immunometabolic Therapy for Inhibition of ccRCC Recurrence After Surgery

Abstract The unique physical tumor microenvironment (TME) and aberrant immune metabolic status are two obstacles that must be overcome in cancer immunotherapy to improve clinical outcomes. Here, an in situ mechano‐immunometabolic therapy involving the injection of a biomimetic hydrogel is presented with sequential release of the anti‐fibrotic agent pirfenidone, which softens the stiff extracellular matrix, and small interfering RNA IDO1, which disrupts kynurenine‐mediated immunosuppressive metabolic pathways, together with the multi‐kinase inhibitor sorafenib, which induces immunogenic cell death. This combination synergistically augmented tumor immunogenicity and induced anti‐tumor immunity. In mouse models of clear cell renal cell carcinoma, a single‐dose peritumoral injection of a biomimetic hydrogel facilitated the perioperative TME toward a more immunostimulatory landscape, which prevented tumor relapse post‐surgery and prolonged mouse survival. Additionally, the systemic anti‐tumor surveillance effect induced by local treatment decreased lung metastasis by inhibiting epithelial‐mesenchymal transition conversion. The versatile localized mechano‐immunometabolic therapy can serve as a universal strategy for conferring efficient tumoricidal immunity in “cold” tumor postoperative interventions.