Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development

Chimeric antigen receptor T cells (CAR-T) therapy has shown great potential in tumor treatment. However, many factors impair the efficacy of CAR-T therapy, such as antigenic heterogeneity and loss, limited potency and persistence, poor infiltration capacity, and a suppressive tumor microenvironment. To overcome these obstacles, recent studies have reported a new generation of CAR-T cells expressing cytokines called armored CAR-T, TRUCK-T, or the fourth-generation CAR-T. Here we summarize the strategies of arming CAR-T cells with natural or synthetic cytokine signals to enhance their anti-tumor capacity. Moreover, we summarize the advances in CAR-T cells expressing non-cytokine proteins, such as membrane receptors, antibodies, enzymes, co-stimulatory molecules, and transcriptional factors. Furthermore, we discuss several prospective strategies for armored CAR-T therapy development. Altogether, these ideas may provide new insights for the innovations of the next-generation CAR-T therapy. [Display omitted] Qiang and colleagues review the advances in fourth-generation CAR-T therapy, which improve the functions of CAR-T itself, enhance supportive immunity, or directly arm CAR-T with tumor-killing payloads. These strategies could be summarized as “CAR+X”—arming CAR-T cells with certain biological payloads and carrying out corresponding functions.