SG33, a Vaccine Strain of Myxoma Virus with Oncolytic Potential, Exploits Macropinocytosis and Clathrin-Mediated Endocytosis for Entry into Pancreatic Cancer Cells

Oncolytic viruses are being investigated as therapeutic agents in cancer, yet their mechanisms of entry into tumor cells remain incompletely understood. We previously showed that SG33, a veterinary vaccinal strain derived from a pathogenic myxoma virus, displays oncolytic activity in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the entry pathways of SG33 into primary PDAC-derived cultures. We found that macropinocytosis, an endocytic process frequently upregulated in PDAC, contributes to SG33 uptake. Moreover, SG33 infection itself induced macropinocytosis in a subset of primary PDAC cultures. Mechanistic studies revealed that phosphatidylserine exposed on the viral envelope promotes SG33 internalization through apoptotic mimicry. In PDAC cultures lacking detectable macropinocytosis, SG33 employed clathrin-mediated endocytosis as an alternative entry route. These findings provide the first insights into the entry mechanisms of SG33 into PDAC-derived cells and indicate that this virus can utilize distinct endocytic pathways depending on the cellular context.