Polyploid cells are frequently observed in human cancers and are positively correlated with malignancy and poor prognosis. Genomic instability and polyaneuploidy which caused by polyploid cells re-enter mitosis and depolyploidization have been well studied, the appropriate microenvironment by which polyploid cells re-enter mitosis has been elusive. Here, taking advantage of our polyploid Drosophila salivary gland imaginal ring tumor model which is driven by polyploid mitosis and depolyploidization and single cell RNA sequencing, we identified essential factors, including JNK, JAK/STAT and Hippo, which provide favorable soil for polyploid cells re-enter mitosis and become tumor. Besides tumor initiation factors, we found that tumor initiating polyploid cells show potential cell polarity defects which makes those cells easily lose cell polarity and become tumor. We further found the tumor initiating polyploid cells enrich cell death signal, such as hid, rpr and Atg8, leading to those ‘‘dangerous cells’’ being eliminated at metamorphosis during normal development. Escaping from cell death of those polyploid cells at the early development stages and tumor situation are largely depended on cell death inhibitor Diap1. Our findings reveal tumor microenvironments that provide a tumor formation soil for polyploid cell tumorigenesis.