Macrophage-targeting combination therapy enhances T-DXd-induced tumor regression

Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach for HER2-positive cancers, with trastuzumab deruxtecan (T-DXd) demonstrating significant efficacy. However, resistance mechanisms often limit the effectiveness of ADC monotherapy. This study explores the potential of combining T-DXd with macrophage-targeting therapies, specifically anti-SIRPα antibodies and PI3Kγ inhibitors, to enhance anti-tumor immunity. Utilizing HER2-positive preclinical models, we hypothesized that this triple combination would synergistically promote immunogenic cell death (ICD) and reprogram tumor-associated macrophages (TAMs). Our results demonstrated that the combination of T-DXd, anti-SIRPα, and IPI-549 significantly inhibited tumor growth compared to monotherapies, with no major weight loss, indicating a favorable tolerability profile. Sequential treatment further enhanced tumor control, achieving complete regression in some cases. Importantly, previously treated mice developed durable immunological memory, completely rejecting subsequent challenges with HER2-expressing tumors. Overall, these findings highlight the therapeutic potential of combining T-DXd with macrophage-targeting strategies as a robust approach to improve the efficacy of immunotherapy in HER2-positive cancers, presenting a promising avenue for clinical development.