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

ABSTRACT

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.