Advanced dual-payload antibody-drug conjugates (DualADCs) for targeted cancer chemo-immunotherapy

Antibody–drug conjugates (ADCs) are a powerful class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. In this study, we developed novel dual-payload ADC (DualADC) platforms that enable co-delivery of a chemotherapeutic agent for direct tumor cell killing and a toll-like receptor agonist to stimulate antitumor immunity. Using triple-negative breast cancer (TNBC) as a model, we established advanced cysteine/lysine co-conjugation strategies optimized for antibody–drug ratio (ADR) and drug–drug ratio (DDR). These refinements minimized hydrophobicity-induced precipitation, enhanced conjugation efficiency, and improved formulation stability. In vivo evaluations in two xenograft mouse models demonstrated strong antitumor efficacy, highlighting the therapeutic potential of DualADCs as a next-generation approach for synergistic chemo-immunotherapy. Overall design: TNBC tumors were collected from syngeneic mouse models at the study endpoint. Total RNA was extracted using the RNeasy Plus Mini Kit following the manufacturer's protocol. cDNA library preparation and bulk RNA sequencing were conducted by Novogene America (Sacramento, CA, USA) using the Illumina HiSeq™ X Ten platform.