Antibody-Mediated Targeting of Secretory Protein SCUBE3 Suppresses Cancer Progression by Inhibiting Oncogenic Signaling and Inducing Antitumor Immunity

Approaches targeting factors that simultaneously promote tumor growth and progression, induce therapy resistance, and inhibit antitumor immunity offer clear benefits over therapies targeting only one of these tumor-promoting processes. Through comprehensive loss-of-function genomic screening, we identified SCUBE3 as a pivotal factor that supports survival and therapy resistance and also orchestrates an immunosuppressive tumor microenvironment. Secretory SCUBE3 supported oncogenic activity through interactions with key oncogenic cell surface receptor proteins, including EGFR, mutant CALR, and TGFβRI/II. These interactions activated the transcription factors FOXR2 and c-Myc, promoting cancer cell proliferation and therapy resistance by enhancing DNA damage repair. Additionally, the SCUBE3-FOXR2 axis created an immunosuppressive tumor microenvironment by facilitating recruitment of the DNMT1 epigenetic repressor complex to the transcription regulator IRF1, thereby inhibiting the expression of MHC-I and MHC-II genes. A first-in-class neutralizing antibody targeting SCUBE3, which was developed using a sophisticated antibody discovery platform and engineered with specific mutations in the heavy chain for enhanced specificity and efficacy, demonstrated profound therapeutic potential across various cancer types in preclinical models, including patient-derived breast and ovarian cancer xenografts. This discovery marks an advancement toward developing a targeted therapy for cancers characterized by hyperactive SCUBE3-associated signaling pathways. SIGNIFICANCE: Targeting SCUBE3 with a neutralizing antibody inhibits tumor growth and metastasis by blocking oncogenic signaling through FOXR2 and c-Myc and by circumventing immunosuppression, providing a promising pan-cancer treatment approach.