Receptor Co‑targeting Strategies for Personalized Ovarian Cancer Therapy

Abstract

Abstract Ovarian cancer remains highly lethal due to late diagnosis, frequent recurrence, and rapid development of resistance to platinum-based chemotherapy. Although rational drug combinations targeting multiple oncogenic pathways hold promise, their clinical utility is often compromised by dose-limiting toxicity and tumor heterogeneity. Antibody-drug conjugates (ADCs) offer an alternative by delivering potent agents directly to tumor cells, thereby reducing systemic toxicity. This approach could be further enhanced by the dual targeting of co-expressed tumor-specific cell surface receptor pairs to broaden tumor coverage and enable the precise delivery of synergistically active drugs. Furthermore, nanotechnology-based carriers extend these concepts by enabling the integration of multiple targeting ligands and payloads into a single drug-delivery platform. Systematic identification and validation of novel co-targeting cell surface receptors, such as G protein-coupled receptors (GPCRs), characterized by high tumor relevance and rapid internalization, may improve tumor coverage and drug uptake in therapy-resistant subpopulations. The outlined strategies are very promising to advance precise and personalized treatment strategies for ovarian cancer. However, dual-receptor approaches remain largely investigational, with limited preclinical validation, and their clinical translation is challenged by receptor heterogeneity, uncertain tumor selectivity, potential off-target effects, and inefficient delivery due to tumor-microenvironment barriers. Furthermore, manufacturing, safety, and regulatory requirements need to be addressed.