Targeting LxCxE Cleft Pocket of Retinoblastoma Protein in Immunosuppressive Macrophages Inhibits Ovarian Cancer Progression

Abstract Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by an immunosuppressive tumor microenvironment (TME) maintained by tumor-associated macrophages (TAM), hindering antitumor responses and immunotherapy efficacy. In this study, we showed that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket caused preferential cell death in Rbhigh M2-polarized or M2-like Rbhigh immunosuppressive TAMs by induction of endoplasmic reticulum stress, p53, and mitochondria-related cell death pathways. A reduction of protumor immunosuppressive macrophages from TME in vivo resulted in enhanced T-cell infiltration and T-cell antitumor response and inhibited cancer progression. We demonstrated increased Rb expression in TAMs in women with ovarian cancer, which was associated with poorer prognosis. Ex vivo, we showed analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from patients with ovarian cancer. Overall, our data identify the therapeutic targeting of the Rb LxCxE cleft pocket as a promising approach for ovarian cancer treatment through depletion of immunosuppressive Rbhigh TAMs and re-shaping of the TME immune landscape.