EGFR-Targeting IgG1 Antibody Enhances NK Cell-Mediated Tumor Killing in KRAS-Mutant Pancreatic Cancer

KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) exhibits intrinsic resistance to epidermal growth factor receptor (EGFR)-targeted therapies owing to constitutive downstream pathway activation. Nevertheless, IgG1 antibodies may retain therapeutic activity through natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), thereby bypassing EGFR downstream signaling. However, whether EGFR-targeted IgG1 antibody-mediated ADCC remains effective in KRAS-mutant PDAC, and what determines therapeutic responsiveness, remain unclear. Here, we investigated whether nimotuzumab-mediated ADCC remains effective despite oncogenic KRAS signaling and explored the determinants of its therapeutic efficacy. Using complementary in vitro and in vivo models, including PDAC cell-NK cell co-culture systems, 3D tumor spheroids, and immunodeficient mouse models (subcutaneous and circulating tumor cell-derived xenografts), we demonstrated that combined nimotuzumab and adoptive NK cell therapy exerts potent antitumor efficacy in PDAC. Mechanistically, this treatment drives robust NK cell functional activation (CD107a/IFN-γ/TNF-α), enhances tumor homing, and induces immunogenic cell death. Collectively, our findings demonstrate that KRAS mutations do not compromise nimotuzumab-mediated ADCC, whereas tumor EGFR expression serves as a predictor of therapeutic responsiveness. Ultimately, this study establishes EGFR-directed NK cell immunotherapy as a promising therapeutic strategy for KRAS-mutant PDAC and provides a rationale for integrating targeted antibodies with cellular immunotherapies in other EGFR-expressing malignancies.