Systematic review of advancements and challenges in NK cell immunotherapy for malignancies

As early as 1863, Virchow observed that cancer often arises at sites of chronic inflammation. Modern epidemiological and clinical studies have confirmed the link between inflammation and cancer. Natural Killer (NK) cells actively participate in and regulate inflammatory processes; however, they are not strictly classified as classic ‘inflammatory cells’ in cellular taxonomy. NK cells rapidly identify and eliminate malignantly transformed cells in a non-major histocompatibility complex (MHC)-restricted manner, a characteristic that distinguishes them from other immune cells. Furthermore, their use in allogeneic settings carries a very low risk of graft-versus-host disease (GvHD), making them ideal candidates for developing ‘off-the-shelf’ cellular immunotherapies. Although early clinical attempts using unmodified NK cells showed limited efficacy, the past decade has witnessed rapid advancements in genetic engineering, cell expansion and differentiation, and synthetic biology, propelling NK cell therapy into a new era of development. This article aims to provide a systematic and multi-dimensional review of the latest research progress in NK cell therapy. We begin by revisiting the core biological basis of NK cell anti-tumor activity, focusing on design strategies, clinical breakthroughs, and bottlenecks of Chimeric Antigen Receptor NK (CAR-NK) cell therapy in hematological malignancies and solid tumors. We delve into antibody-based NK cell recruitment strategies (such as BiKEs/TriKEs) and techniques to enhance antibody-dependent cellular cytotoxicity (ADCC), and analyze cytokine-induced memory-like NK (CIML-NK) cells as a non-gene editing enhancement strategy. Simultaneously, we focus on the core challenges currently faced by NK cell therapies, particularly in solid tumors, including poor tumor infiltration, potent suppression by the tumor microenvironment (TME), and limited in vivo persistence. We summarize diversified synergistic strategies, such as combination with immune checkpoint inhibitors, radiotherapy, chemotherapy, targeted drugs, and direct modifications of the TME. Finally, this article discusses contentious points within the field and provides a forward-looking perspective on future directions, striving to offer a comprehensive and insightful reference for the translation of NK cell therapy from the laboratory to widespread clinical application.