Breast Cancer: Challenges in the Treatment and Prodrug Strategies

Breast cancer (BC) remains a leading cause of mortality worldwide, with treatment complicated by tumor heterogeneity, drug resistance, and therapy-related toxicities. Despite advances in chemotherapy, immunotherapy, and surgery, these challenges continue to limit therapeutic outcomes. Among emerging strategies, prodrugs have shown promise. These pharmacologically inactive compounds are designed to undergo enzymatic or chemical conversion in the body, releasing the active drug selectively in target tissues, thereby improving drug delivery, enhancing efficacy, and reducing systemic toxicity. Prodrug strategies targeting specific molecular features of tumors, such as the tumor microenvironment (TME), offer potential solutions to issues like poor drug solubility and bioavailability. Combining prodrugs with other therapeutic modalities, including immunotherapy and precision medicine, is actively being investigated to overcome drug resistance and enhance treatment response. Nevertheless, challenges remain, including the complexity of designing prodrugs that can be efficiently activated within the TME, as well as scalability and manufacturing costs. Future research leveraging nanotechnology, personalized medicine, and artificial intelligence-driven drug discovery is expected to drive innovations in prodrug-based therapies. Integrating these approaches may enable more effective and individualized treatments for BC, particularly in cases refractory to conventional therapies. This review highlights the current status, challenges, and future directions of prodrug development in breast cancer therapy, underscoring their potential to transform the treatment landscape.