PHERON · Photodynamic Hydrogel for Encapsulated Release and Organoid-based Neu5Ac desialylation

Colorectal cancer (CRC) was estimated to be the second most commonly diagnosed cancer in Europe. CRC can be classified into subtypes based on distinct molecular and clinical features, termed consensus molecular subtypes (CMS 1-4). The proportion of CMS4 was 38.5% in CRC stage IV patients, only 6% of whom had a 5-year survival rate. CMS4 CRC is highly malignant and characterized by a richness of stromal fibroblasts and, consequently, an increased expression of mesenchymal genes. The sialylation of CRC stromal cells, as well as tumor cells and fibroblasts, has been verified as a key factor in forming the immunosuppressive tumor microenvironment (TME), which is also the main challenge for immunotherapy responses. Establishing multicellular CMS4 CRC spheroids helps unravel the mechanism of CRC TME and test the drug efficacy.3Fax-Peracetyl Neu5Ac (SI) is a sialyltransferase inhibitor capable of reversing sialylation in the TME. It can disrupt the immunosuppression of TME through desialylation and thus activate T cells and natural killer cells (NK cells). A growing body of evidence has proven that sialylation-included glyco-immune checkpoints are more widespread in tumor tissue and have a greater potential for application than PD-1/PD-L1 and CTLA-4 inhibitors currently in use. Notwithstanding, nephrotoxicity remains an unsolved problem in its application.PHERON aims to develop a photodynamic liposomes-encapsulated hydrogel to achieve the controlled release of SI at the colorectal tumor site, through a novel CRC multicellular spheroid model.