Immune Reprogramming of Tumor Microenvironments by Cytotoxic Antibody–Drug Conjugate Payloads

Antibody-drug conjugates (ADC) have recently emerged as an effective treatment option for cancer. Although the fundamental mechanisms of direct tumor cell killing by various ADC payloads have been established, their impact on the tumor microenvironment (TME) remains underexplored. To investigate this fundamental question, we generated an immunocompetent murine tumor model that maintains the expression of a clinically validated tumor-associated antigen, human HER2. We evaluated two ADCs with a shared antibody framework: trastuzumab linked to the microtubule inhibitor monomethyl auristatin E (T-MMAE) and the topoisomerase inhibitor deruxtecan (T-DXd). Treatment with T-MMAE led to a significant increase in immune cell infiltration, whereas T-DXd-treated tumors had fewer immune cells albeit comparable tumor cytotoxicity. When combined with anti-PD-1 immunotherapy, similar additive effects on the primary antitumor response were observed for both ADCs. A key qualitative difference between the two ADCs was observed in the phenotypes of myeloid APCs; T-MMAE treatment resulted in greater immune cell infiltration within the tumor, including macrophages that showed increased gene expression of F4/80, CD206, and IL10RA. In contrast, tumors treated with T-DXd exhibited a lower proportion of macrophages, but APCs in these tumors displayed heightened levels of the CD80 costimulatory molecule. The secondary antitumor response mediated by memory CD8+ T cells was crucial for the formation of immunologic memory induced by both ADCs. Therefore, our findings reveal that, after ADC-mediated tumor cytotoxicity, different ADC payloads elicit distinct immunologic responses characterized by varying levels of myeloid cell activation within the TME.