A Chemoimmunotherapy Nanogel Enables Efficient Delivery of Interleukin‐2 and Induction of Immunogenic Cell Death for Effective Cancer Therapy
Hsuan‐Yu Mu, Yen‐Nhi Ngoc Ta, Max Jing Rui Tham, Fu‐Fei Hsu, Yu‐Chieh Lin, Hsi‐Chien Huang, Yun‐Chieh Sung, Chih‐I Huang, Ching-Ling Wu, Chao‐Hung Chang, Sheng Yang, Tsung‐Ying Lee, Dehui Wan, Jane Wang, Dan G. Duda, Yves Boucher, Jen‐Huang Huang, Wee Han Ang, Yunching Chen
Abstract
Abstract Interleukin‐2 (IL‐2) is one of the first FDA‐approved immunotherapeutics, but its use is limited by toxicity and low efficacy. In addition, all immunotherapies are limited by the immunosuppressive and desmoplastic microenvironment of “immunologically cold” tumors, such as pancreatic ductal adenocarcinoma (PDAC) or hepatocellular carcinoma (HCC) with advanced liver fibrosis. Here, a new chemoimmunotherapy nanogel (IL2‐Pt@Nanogel) for dual delivery of IL‐2 and the type II immunogenic cell death inducer Pt‐NHC that reduces the immunosuppressive phenotype of tumor‐associated macrophages and diminishes regulatory T cell infiltration by inducing the production of type I interferon (IFN) by cancer cells is reported. Combining the angiotensin II receptor blocker losartan with IL2‐Pt@Nanogel treatment reduces desmoplasia and reprogrammes the microenvironment of PDAC and HCC toward an immunostimulatory one. These effects result in potent anti‐tumor efficacy in models of primary and metastatic PDAC and HCC with underlying liver fibrosis. This study presents a strategy for IL‐2‐based chemoimmunotherapy with the potential for clinical translation to treat solid tumors.