BRCA1 is one of the most frequently-mutated tumor suppressor genes in ovarian and breast cancers. Loss of BRCA1 triggers homologous recombination (HR) repair deficiency, consequently leading to genomic instability and PARP inhibitors (PARPi)-associated synthetic lethality. Although, the roles of BRCA1 in DNA repair and replication have been extensively investigated, its tumor suppressive functions beyond genome safeguard remain poorly understood. Here, we report that BRCA1 promotes ferroptosis susceptibility through catalyzing K6-linked polyubiquitination of GPX4 and subsequently accelerating GPX4 degradation. Depletion of BRCA1 induces ferroptosis resistance in ovarian cancer cells due to elevated GPX4 protein, and silence of GPX4 significantly suppresses the growth of BRCA1-deficient ovarian cancer xenografts. Importantly, we found that PARPi triggers ferroptosis in ovarian cancer cells, inhibition of GPX4 markedly increase PARPi-induced ferroptosis in BRCA1-deficient ovarian cancer cells. Combined treatment of GPX4 inhibitor and PARPi produces synergistic anti-tumor efficacy in BRCA1-deficient ovarian cancer cells, patient derived organoid (PDO) and xenografts. Thus, our study uncovers a novel mechanism via which BRCA1 exerts tumor suppressive function through regulating ferroptosis, and demonstrates the potential of GPX4 as a therapeutic target for BRCA1-mutant cancers.

Malignant pleural effusion (MPE) and malignant ascites (MA) are common complications of malignant tumors, often indicating that the malignant tumors have reached an advanced stage, leading to a shorter survival. Historical studies have shown that the effusion or asities are deficient in innate immunity and/or adaptive immunity. It would be a high therapeutic value if the immune status (deficiency or exhaustion) in this tumor microenvironment can be corrected using innate and adaptive immune targeting molecules. Here we have studied the immune status of one MPE sample from an advanced Her2 positive breast cancer patient and one MA sample from an advanced ovarian cancer patient; and used a novel trispecific molecule targeting Her2, macrophage and NK cell (IAMA-004) and a novel Fc-cytokine fusion protein (IAMA-005) to treat the cells from MPE or MA samples to determine the efficacy in the killings of tumor cells and the modulation of IFN-g and Granzyme B levels.