Targeting triple-negative breast cancer: Molecular basis and emerging antibody-drug conjugate strategies.

Abstract

Triple-negative breast cancer (TNBC) accounts for ~10-15% of all breast cancers and is an aggressive, molecularly heterogeneous subtype associated with poor clinical outcomes and limited targeted treatment options. Consequently, systemic therapy has historically relied on chemotherapy, which is often compromised by recurrence, dose-limiting toxicity, and the rapid development of therapeutic resistance. Antibody-drug conjugates (ADCs) have emerged as a transformative therapeutic platform by combining tumor-specific antibody targeting highly potent cytotoxic payloads through advances in antibody engineering, linker chemistry, and payload design. This mini-review summarizes recent advances in ADC development for TNBC, with a particular focus on the molecular basis of ADC therapy, the chemical determinants governing efficacy and selectivity, emerging mechanisms of resistance, and next-generation strategies to improve therapeutic durability and clinical outcomes.