Abstract
Antibody–drug conjugates (ADCs) have revolutionized targeted cancer therapy, yet a fundamental clinical contradiction remains: while some ADCs require strict companion diagnostic testing, others demonstrate robust efficacy in biomarker-negative tumors. This review investigates the underlying mechanisms of this discrepancy, proposing that ADC linker cleavability is the primary determinant of both biomarker dependence and systemic toxicity profiles. By analyzing data from 40 clinical trials encompassing 7879 patients, we observed a distinct dichotomy based on linker design. ADCs utilizing noncleavable linkers function in a strictly biomarker-dependent manner, correlating with a targeted safety profile (34% severe toxicity rate) but relying entirely on antigen-mediated internalization. Conversely, ADCs with cleavable linkers facilitate premature payload release in the systemic circulation and tumor microenvironment. This enables a potent, biomarker-independent bystander effect—achieving a 29.7% tumor response rate even without target expression—but at the cost of significantly increased off-target systemic toxicities (47% severe toxicity rate). Recognizing this inherent trade-off between antitumor potency and safety, we further explore the development of next-generation, conditionally cleavable linkers. These advanced platforms are engineered for selective activation exclusively within the tumor microenvironment. We conclude that transitioning towards conditionally released linkers is essential to balance efficacy and systemic toxicity, optimizing the therapeutic index and fully realizing the potential of the “magic bullet.”