PDF(Pubmed)
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.
摘要：
独特的物理肿瘤微环境（TME）和异常的免疫代谢状态是癌症免疫治疗中必须克服的两个障碍，以改善临床结果。这里,涉及注射仿生水凝胶的原位机械免疫代谢疗法与抗纤维化剂吡非尼酮的顺序释放有关，软化坚硬的细胞外基质，和小干扰RNAIDO1，它破坏犬尿氨酸介导的免疫抑制代谢途径，与多激酶抑制剂索拉非尼一起，诱导免疫原性细胞死亡。该组合协同增强肿瘤免疫原性并诱导抗肿瘤免疫。在透明细胞肾细胞癌的小鼠模型中，肿瘤周围单剂量注射仿生水凝胶促进了围手术期TME向更具免疫刺激性的方向发展，可以防止肿瘤术后复发并延长小鼠生存期。此外,局部治疗诱导的全身抗肿瘤监测作用通过抑制上皮-间质转化减少肺转移。通用的局部机械免疫代谢疗法可以作为在“冷”肿瘤术后干预中赋予有效的肿瘤杀伤免疫的通用策略。
