%0 Journal Article
%T Biomimetic Hydrogel-Mediated Mechano-Immunometabolic Therapy for Inhibition of ccRCC Recurrence After Surgery.
%A Dong Y
%A Luo J
%A Pei M
%A Liu S
%A Gao Y
%A Zhou H
%A Nueraihemaiti Y
%A Zhan X
%A Xie T
%A Yao X
%A Guan X
%A Xu Y
%J Adv Sci (Weinh)
%V 11
%N 30
%D 2024 Aug 17
%M 38884220
%F 17.521
%R 10.1002/advs.202308734
%X 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.