Disitamab vedotin triggers ferroptosis to activate CD8+ T-cell antitumor immunity in HER2-expressing breast cancer

Abstract Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly aggressive and is associated with poor prognosis after metastasis or recurrence. The development of anti-HER2 antibody–drug conjugates (ADCs) has markedly improved outcomes. Disitamab vedotin (RC48) is a novel anti-HER2 ADC that exhibits antitumor activity against both HER2-positive and HER2-low breast cancers, although its molecular mechanism of action remains incompletely understood. Here, we show that RC48 triggers the accumulation of lipid reactive oxygen species (ROS), thereby inducing ferroptosis and the subsequent release of damage-associated molecular patterns (DAMPs) that initiate immunogenic cell death (ICD). DAMP emission promotes dendritic cell maturation and increases CD8 + T-cell infiltration and cytotoxicity within the tumor microenvironment. In vivo mouse models confirm the efficacy and safety of RC48 both as a monotherapy and as part of a combination therapy with anti-programmed cell death ligand 1 (PD-L1). Collectively, our findings delineate a ferroptosis–ICD–immune axis underlying the antitumor activity of RC48 and support its clinical development as a monotherapy or in combination with immune checkpoint inhibitors for HER2-expressing breast cancer.