Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy

BACKGROUND: CAR-T cell therapy represents a major breakthrough in hematological malignancies. However, the trade-off between insufficient treatment persistence and treatment-related toxicities (especially cytokine release syndrome, CRS) still limits its wider clinical application. MAIN BODY: Our review aims to reframe the understanding of this central dilemma. It posits that the dynamic imbalance of intracellular signaling networks and external inflammation in the tumor microenvironment (TME) are the causes of insufficient persistence of CAR-T cells and the severe CRS. The intracellular signaling network and the influence of the external TME jointly regulate CAR-T cell persistence and inflammatory response. We explore strategies for designing CAR-T cells that simultaneously enhance persistence and mitigate severe CRS risk. The next-generation goal is to achieve an optimal therapeutic outcome in which CAR-T cells exhibit sustained antitumor efficacy alongside a favorable safety profile. CONCLUSION: The central thesis posits that persistence and safety do not have to be chosen one at the expense of the other. Rather, the relationship between persistence and CRS exists in harmony. Through the precise modulation, it is feasible to simultaneously enhance CAR-T cell persistence while effectively mitigating CRS. This review paints a blueprint for the next-generation CAR-T cell therapies that are both more persistent and inherently safer.