BC is one of the most common malignant tumors among women worldwide, with characteristics of high molecular heterogeneity and evolving drug resistance mechanisms.1 Although conventional chemotherapy, endocrine therapy, and monoclonal antibody (mAb)-targeted therapy have substantially improved patient survival, issues such as the toxic side effects of the chemotherapy and the acquired resistance to endocrine and targeted agents continue to limit their long-term efficacy.[2], [3], [4] Therefore the development of novel therapeutic strategies capable of enhancing tumor specificity, mitigating systemic toxicity, and effectively overcoming drug resistance is imperative.

ADCs represent a significant advancement in targeted therapy by integrating the target specificity of mAbs with potent cytotoxic drugs. This design significantly enables drug accumulation in tumor tissues while reducing toxicity to normal tissues, thereby improving patient survival rates.5 In BC treatment, representative ADCs such as ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd) have demonstrated notable clinical success.[6], [7] However, as a complex biochemical system, any functional abnormality in any component of the ADC can lead to resistance. Their broad clinical application is constrained by multifactorial resistance mechanisms, including antigen–antibody-related resistance, drug efflux pump overexpression, and others.[8], [9], [10]

With the growing maturity and widespread application of ADC technology and a deeper understanding of its intrinsic limitations, broader paradigms of drug conjugates have emerged, marking a paradigm shift in targeted conjugate therapeutics.[11], [12] These emerging drug conjugates retain the targeted delivery concept of ADCs while integrating diverse innovative payloads, such as proteolysis-targeting chimeras (PROTACs), small interfering RNAs (siRNAs), immunomodulators, or novel targeted carriers (e.g. peptides, small molecules). This expansion confers unique advantages, such as the catalytic degradation of traditionally undruggable targets, multitarget modulation, and tumor immune microenvironment remodeling, to offer promising therapeutic strategies for refractory/resistant BC and other malignancies.[12], [13], [14] The major classes of targeted drugs that are approved or under clinical trials for BC therapy are schematically illustrated in Fig. 1.

In this review, we systematically delineate the key molecular mechanisms underlying drug resistance in ADC-based BC therapy and evaluate both achievements and limitations of current approaches. Building on this foundation, we focus on the emerging drug conjugates that have entered clinical trials for BC, and conduct in-depth analyses of their molecular structural characteristics and antitumor mechanisms, which might confer unique advantages for overcoming drug resistance. Additionally, we analyze associated technical challenges and optimization strategies in drug conjugates. This review aims to offer novel pharmacological perspectives and strategies for advancing drug conjugate development and circumventing therapeutic resistance in BC.