Challenges and opportunities beyond antibody-drug conjugates: Toward a new era of programmable therapeutic proteins

The development of targeted therapies is a central focus of modern oncology and personalized medicine. Among current platforms, antibody-drug conjugates (ADCs) remain the most established, combining the specificity of monoclonal antibodies with the potent cytotoxicity of small molecules. Despite remarkable clinical success, ADCs face fundamental limitations, including high cost, reliance on eukaryotic production systems, molecular heterogeneity, systemic toxicity, and narrow therapeutic windows. These challenges have motivated the search for alternatives more compatible with scalable and standardized biotechnology. This review summarizes current achievements and unresolved issues in ADC development, while emphasizing innovative directions based on fully genetically encoded protein constructs. Particular focus is given to dual-function chimeric proteins that integrate scaffold-based targeting domains with peptide-derived cytotoxic modules, notably anticancer peptides. Such molecules combine high selectivity, compact structure, low immunogenicity, and compatibility with bacterial expression, making them attractive for both production and therapy. We further highlight enabling technologies, including synthetic biology, display systems, and machine learning, that accelerate the discovery and optimization of these constructs. Together, these approaches provide the foundation for next-generation protein therapeutics. The strategies discussed here outline not only a scientific concept but also a biotechnological framework for developing standardized and accessible treatments tailored to individual tumor profiles.