The Feasibility of Using CRISPR-Cas9 to Knock Out IL-6 Receptor in CAR-T Cells to Mitigate Cytokine Release Syndrome in Cancer Therapy

Cytokine release syndrome (CRS) is a common complication associated with chimeric antigen receptor T cell (CAR-T) therapy, primarily driven by excessive interleukin-6 (IL-6) production. Although the use of IL-6 inhibitors and corticosteroids can partially alleviate CRS, these approaches often yield limited success and may compromise CAR-T cell functionality. Recent advancements in gene-editing technologies, particularly CRISPR-Cas9, offer significant opportunities by enabling site-specific knockout of the IL-6 receptor (IL-6R) in CAR-T cells. In vitro studies have demonstrated that IL-6 gene deletion substantially reduces CRS-related inflammatory responses while preserving the anti-tumor capabilities of CAR-T cells. This strategy not only addresses inflammation at its source but also mitigates harmful systemic inflammatory responses, thereby improving therapeutic outcomes. This review highlights the pivotal role of IL-6 in CRS pathophysiology, the shortcomings of conventional treatment strategies, and the potential of genome-editing approaches such as IL-6R knockout. By precisely targeting the root causes of IL-6-mediated inflammation, this approach aims to optimize both the efficacy and safety of CAR-T cell therapy.