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Background Antibody-drug conjugates (ADCs) have emerged as a valuable class of targeted cancer therapies by selectively delivering cytotoxic payloads to tumor cells. However, their efficacy can be limited in tumors with low antigen expression, tumor cell heterogeneity, or acquired resistance.Methods To address these challenges, we are developing dual-payload ADCs, including immunostimulatory ADCs (iADCs), which simultaneously deliver both a cytotoxin and an immune stimulator directly to the tumor cells. This dual-action approach aims to enhance therapeutic potency by debulking tumors via the cytotoxic payload while engaging the immune system with the immune stimulator payload and has the potential to overcome emerging resistance mechanisms towards the single payload ADC.Results The preclinical pharmacology data demonstrate that iADCs offer superior in vitro and in vivo efficacy compared to conventional, single-payload ADCs, with favorable pharmacokinetics and molecular stability. Specifically, an exatecan/STING agonist dual-payload anti-HER2 iADC elicited significantly improved antitumor activity than either single payload ADCs alone, accompanied by strong immune cell activation in the tumor microenvironment. Notably, complete responders exhibited durable immune memory, effectively rejecting MC38-HER2 tumors in rechallenge experiments. Furthermore, iADCs were well tolerated in non-human primates at 25 mg/kg administered every three weeks for two doses (Q3W ×2), indicative of a favorable safety profile and supporting advancement towards clinical development.Conclusions These findings highlight the potential of iADCs as a novel treatment option that integrates targeted cytotoxicity with immune engagement, offering a promising approach to address resistance and improve long-term outcomes in cancer treatment.