Current development and challenges of NK cell-based immunotherapy for gastrointestinal cancers

Despite multimodal treatment options, most gastrointestinal (GI) cancers remain associated with high mortality rates and poor responsiveness to immunotherapy. The remarkable success of immune cell-based therapies in hematologic malignancies has raised interest in translating adoptive cell therapies to GI cancers. Among these approaches, natural killer (NK) cell-based therapies offer potent cytotoxicity, and a favorable safety profile. Multiple NK cell platforms are now under preclinical and clinical development, demonstrating encouraging therapeutic efficacy in GI malignancies. Nevertheless, challenges such as limited in vivo persistence, immunosuppressive tumor microenvironment (TME), and heterogeneous expression of NK cell therapy targeted antigens continue to limit therapeutic benefit. Recent advances are being explored to overcome these barriers and enhance NK cell persistence and specificity. This review summarizes recent progress in NK cell-based immunotherapy for GI cancers, highlights representative clinical trials, and discusses strategies to improve efficacy and durability. With continued innovation, NK cell-based therapy holds promise to become an essential component of the future immunotherapy landscape for GI malignancies.