A Chemoimmunotherapy Nanogel Enables Efficient Delivery of Interleukin-2 and Induction of Immunogenic Cell Death for Effective Cancer Therapy

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. IL2-Pt@Nanogel, a chemoimmunotherapy nanogel delivering IL-2 and Pt-NHC, diminishes the immunosuppressive phenotype of tumor-associated macrophages and reduces regulatory T cell infiltration. When combined with the angiotensin II receptor blocker, losartan, this nanogel reduces desmoplasia and shifts the PDAC and HCC microenvironments towards an immunostimulatory state. This approach has shown significant anti-tumor efficacy in primary and metastatic PDAC and HCC models, indicating a promising IL-2-based chemoimmunotherapy strategy for solid tumor treatment.image