Interleukin-enhanced CAR-engineered immune cells in tumor immunotherapy: current insights and future perspectives

Despite the remarkable clinical success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies, the therapeutic efficacy of conventional second-generation CAR-T cells in treating solid tumors remains suboptimal, primarily due to three major biological barriers: (1) the immunosuppressive tumor microenvironment (TME), (2) inadequate tumor infiltration capacity, and (3) T cell exhaustion mechanisms. To overcome these limitations, innovative fourth-generation “armored” CAR-T cell platforms have been engineered with integrated cytokine-secreting modules designed to potentiate anti-tumor responses through localized immunomodulation. These advanced cellular therapeutics achieve targeted delivery of various immunostimulatory cytokines directly within the TME, thereby orchestrating three critical therapeutic effects: (I) remodeling of the immunosuppressive niche, (II) enhancement of immune cell persistence, and (III) neutralization of immunosuppressive signaling networks. This comprehensive review systematically examines the translational applications of cytokine-secreting CAR-engineered immune cells, including CAR-T, CAR-NK, and CAR-iNKT cell platforms, in solid tumor immunotherapy, with particular emphasis on multiple classes of immunomodulatory cytokines that enhance cytotoxic potential, promote immune cell survival, and counteract TME-mediated immunosuppression. We critically evaluate preclinical and clinical evidence demonstrating the therapeutic efficacy of cytokine-armed CAR-engineered cells across various tumor models, including hematological malignancies, glioblastoma, and neuroblastoma. Furthermore, this review addresses current translational challenges, particularly cytokine-associated toxicity profiles and innovative strategies for achieving spatiotemporal control of cytokine release, while discussing their potential implications for advancing clinical outcomes in solid tumor immunotherapy.