Synthetic Biology in the Engineering of CAR-T and CAR-NK Cell Therapies: Facts and Hopes.

The advent of modern synthetic-biology tools has enabled the development of cellular treatments with engineered specificity, leading to a new paradigm in anticancer immunotherapy. T cells have been at the forefront of such development, with six chimeric antigen receptor-modified T-cell products approved by the FDA for the treatment of hematologic malignancies in the last 5 years. Natural killer (NK) cells are innate lymphocytes with potent cytotoxic activities, and they have become an increasingly attractive alternative to T-cell therapies due to their potential for allogeneic, "off-the-shelf" applications. However, both T cells and NK cells face numerous challenges, including antigen escape, the immunosuppressive tumor microenvironment, and potential for severe toxicity. Many synthetic-biology strategies have been developed to address these obstacles, most commonly in the T-cell context. In this review, we discuss the array of strategies developed to date, their application in the NK-cell context, as well as opportunities and challenges for clinical translation.

Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism.

T cells engineered to express chimeric antigen receptors (CARs) have shown remarkable success in treating B-cell malignancies, reflected by multiple US Food and Drug Administration-approved CAR-T cell products currently on the market. However, various obstacles have thus far limited the use of approved products and constrained the efficacy of CAR-T cell therapy against solid tumors. Overcoming these obstacles will necessitate multidimensional CAR-T cell engineering approaches and better understanding of the intricate tumor microenvironment (TME). Key challenges include treatment-related toxicity, antigen escape and heterogeneity, and the highly immunosuppressive profile of the TME. Notably, the hypoxic and nutrient-deprived nature of the TME severely attenuates CAR-T cell fitness and efficacy, highlighting the need for more sophisticated engineering strategies. In this review, we examine recent advances in protein- and cell-engineering strategies to improve CAR-T cell safety and efficacy, with an emphasis on overcoming immunosuppression induced by tumor metabolism and hypoxia.

T cells to fix a broken heart.

In vivo engineered T cells provide a promising approach to treat cardiac diseases.