...Our study shows that Doxo-induced senescent fibroblasts yield several SASP factors and exhibit increased autophagy. Interestingly, Quercetin, a bioactive flavonoid, reduces autophagy, increases ER stress, and partially triggers senescent fibroblast death. Given the role of senescent cells in cancer progression, we tested the effect of conditioned media from untreated and quercetin-treated senescent fibroblasts on osteosarcoma cells to determine whether senolytic treatment affected tumour cell behaviour. We report that the partial senescent fibroblast clearance, achieved by quercetin, reduced osteosarcoma cell invasiveness, curbing the pro-tumour effects of senescent cells. The reduction of cell autophagic activity and increased ER stress, an undescribed effect of quercetin, emerges as a new vulnerability of Doxo-induced senescent fibroblasts and may provide a potential therapeutic target for cancer treatment and suggest novel drug combinations as a promising strategy against the tumour.