Evolving antibody-drug conjugates in breast cancer from precision delivery to tumor microenvironment reprogramming.

Abstract

Antibody-drug conjugates (ADCs) have emerged as an important therapeutic strategy for breast cancer, particularly in the context of its molecular heterogeneity. Initially developed as targeted cytotoxic delivery systems, ADCs are increasingly being explored as multifunctional platforms that may also influence the tumor microenvironment (TME). The expansion of ADC targets beyond human epidermal growth factor receptor 2 (HER2) to include molecules such as trophoblast cell surface antigen 2 (TROP-2) and human epidermal growth factor receptor 3 (HER3) has broadened the therapeutic landscape, offering new options for subtypes with limited targeted therapies, including triple-negative breast cancer (TNBC).Accumulating evidence suggests that the tumor microenvironment plays a critical role in modulating ADC efficacy and resistance. Physical barriers, immunosuppressive signaling, and stromal interactions may limit drug penetration and therapeutic response. In parallel, ADC-induced cytotoxicity has been associated with immunogenic cell death and potential remodeling of the tumor immune milieu. These insights have prompted the development of improved ADC designs, including environment-responsive linkers, optimized payloads, and rational combination strategies with immunotherapy.In this review, we summarize the evolving landscape of ADC development in breast cancer, focusing on target expansion, structural optimization, resistance mechanisms, and interactions with the tumor microenvironment. We also discuss emerging strategies aimed at enhancing therapeutic efficacy and overcoming resistance, highlighting growing interest in integrating targeted cytotoxicity with modulation of the tumor microenvironment.