TGF-β-mediated suppression of NK cell function and targeting strategies in tumor immunotherapy

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that can directly kill tumor cells or coordinate other immune cells to exert antitumor effects. Transforming growth factor-β (TGF-β) is a potent inhibitory cytokine in the tumor microenvironment (TME), and its suppression of NK-cell function is an important contributor to tumor immune evasion. TGF-β can inhibit NK-cell activation and effector functions, impair NK-cell proliferation and migration, and induce the conversion of NK cells into type 1 innate lymphoid cells (ILC1s). Therefore, blocking or "hijacking" TGF-β signalling is a promising strategy to enhance the therapeutic efficacy of NK-cell-based immunotherapy. In preclinical models and, to a lesser extent, in early-phase clinical trials of TGF-β pathway inhibitors, strategies to reverse TGF-β-mediated suppression mainly include delivery of small-molecule inhibitors and recombinant protein drugs targeting TGF-β and its signalling pathways, as well as genetic engineering of NK cells. This review summarizes TGF-β signal transduction, the antitumor biological functions of NK cells, the multifaceted inhibitory effects of TGF-β on NK cells within the TME, and NK-cell-based tumor immunotherapy approaches that target TGF-β. We further highlight the limitations of current strategies and point to future directions for more precise and controllable interventions.