Activation of FcγR and classical complement pathways contribute to T-DXd plus pertuzumab therapeutic efficacy

In addition to delivering cytotoxic payloads, HER2-targeted antibody–drug conjugates (ADCs) can engage innate immune effector pathways (such as FcγR and complement) similar to monoclonal antibodies (mAbs). However, the relative contribution of innate pathways to therapeutic benefit remains unclear, especially in cases where ADCs are combined with mAbs. To address this question, we performed analysis of bulk clinical transcriptomic datasets that revealed higher baseline expression of C1q and FcγR genes, likely representing intratumoral macrophage, monocyte, and neutrophil transcription, was associated with greater benefit from HER2-targeted mAb and ADC regimens. Mechanistic studies validated these findings, demonstrating that trastuzumab deruxtecan (T-DXd) and pertuzumab each induced robust FcγR-dependent ADCC and ADCP, and together cooperatively activated C1q-dependent classical complement pathway. Consistent with these mechanisms, the efficacy of T-DXd plus pertuzumab was diminished in FcγR-deficient or C1q-deficient in vivo models. These findings implicate FcγR and classical complement as key contributors to T-DXd plus pertuzumab efficacy and suggest C1q/FcγR expression signatures as potential biomarkers to predict treatment response.