The fourth iteration of CARs, termed "TRUCKs," was modeled after second-generation CARs. TRUCKs feature a gene expression cassette that can be activated to produce a transgenic cytokine (Fig. ) . Cytokines, including IL-12, are delivered directly to the tumor to improve immune response . TRUCKs can minimize systemic side effects commonly associated with widespread cytokine release, such as CRS, by producing cytokines near the tumor. After the initial CAR-T cell response, tumor relapse can occur if CAR-T cells fail to detect cancer cells with minimal receptor expression . As a result, secretion of inducible IL-12 from TRUCKs brings immune cells toward the microenvironment to eradicate remaining parts of the tumor . Stimulating cytokines alters the tumor microenvironment and leads to prolonged activation of CARs and shields overactive T cells from programmed cell death, thus increasing persistence . Finally, fifth-gen CARs include an interleukin-2 receptor β-chain domain and a binding location for STAT3 (Fig. ) . This structure contributes to strong cytokine (JAK-STAT3/5) signaling within the specific tumor sites while minimizing systemic side effects . IL-2 signaling influences two important aspects of immune response: T cell differentiation and memory recall responses . Fifth-generation CAR modifications contribute to improved T cell activation, persistence, and proliferation through cytokine-mediated signaling pathways . The 5th generation is the most recent and advanced iteration of CARs, but more clinical trials are necessary to ensure its safety and efficacy.