Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

Simple Summary Cell therapy over the last few years has revolutionized the treatment of blood cancers. However, efficacy against cancers of solid organs remains limited. These cancers pose a major challenge to the success of cell therapy by generating a suppressive environment that inhibits immunity. We review current efforts to improve the potency of natural killer (NK) cell therapy in the tumor microenvironment. The successful application of these approaches will lead to more effective treatment options and improve clinical outcomes for patients with solid cancers. Natural killer (NK) cells are innate immune effectors capable of broad cytotoxicity via germline-encoded receptors and can have conferred cytotoxic potential via the addition of chimeric antigen receptors. Combined with their reduced risk of graft-versus-host disease (GvHD) and cytokine release syndrome (CRS), NK cells are an attractive therapeutic platform. While significant progress has been made in treating hematological malignancies, challenges remain in using NK cell-based therapy to combat solid tumors due to their immunosuppressive tumor microenvironments (TMEs). The development of novel strategies enabling NK cells to resist the deleterious effects of the TME is critical to their therapeutic success against solid tumors. In this review, we discuss strategies that apply various genetic and non-genetic engineering approaches to enhance receptor-mediated NK cell cytotoxicity, improve NK cell resistance to TME effects, and enhance persistence in the TME. The successful design and application of these strategies will ultimately lead to more efficacious NK cell therapies to treat patients with solid tumors. This review outlines the mechanisms by which TME components suppress the anti-tumor activity of endogenous and adoptively transferred NK cells while also describing various approaches whose implementation in NK cells may lead to a more robust therapeutic platform against solid tumors.