Degradation-coupled antibody conjugates for precision cancer therapy.

Antibody-drug conjugates (ADCs) are an important class of targeted cancer therapeutics that selectively deliver potent cytotoxic payloads to tumor cells through antibody-mediated targeting. However, the efficacy of some ADCs can be limited by inefficient target protein (e.g., membrane receptor) internalization and lysosomal trafficking, which determine intracellular payload release. In addition, persistent disease-driving proteins sustain oncogenic signaling, promoting tumor progression and therapeutic resistance. Recent advances in targeted protein degradation (TPD) offer a strategy to overcome these limitations by controlling the trafficking and degradation fate of target proteins. Building on the limitations of ADCs and the capabilities of TPD, we propose degradation-coupled antibody conjugates, a conceptual framework that integrates degradation-driven programmable protein fate control with antibody conjugates to enhance payload delivery and expand therapeutic functionality.