Senolytic drugs dasatinib and quercetin promote skin papilloma progression by eliminating senescent cells and impairing immune surveillance

Cellular senescence can function as a cell defense mechanism in halting tumorigenesis. It can also promote tumor progression through senescence-associated secreted phenotype (SASP). Yet how these two opposite pathophysiological processes play a role in the tumor microenvironment (TME) homeostasis remains elusive. Senolytics, exemplified by employing Dasatinib and Quercetin (D+Q), are designed to eliminate senescent cells in vivo in alleviating age-related diseases, but their impacts on tumor progression are much less understood. Here, using a DMBA/TPA-induced skin papilloma model in wild-type or IGF-1 transgenic mice, we found that while D+Q treatment promotes the transition of hyperplasia to papilloma, concomitant with reduced senescent cells in wild-type mice, it dramatically facilitates initiation and progression of papilloma in IGF-1 Tg mice, accompanied by elimination of senescent cells. Unexpectedly, we found that D+Q treatment leads to elevated PD-L1 expression and reduced CD8⁺ T cell and F4/80⁺ macrophage infiltration in B16-F10 syngeneic tumors. These results indicate that the overriding senescence is vital in skin papilloma progression and that senolytic drugs Dasatinib and Quercetin promote skin papilloma progression by eliminating senescent cells and impairing immune surveillance.