Wang Min, Wang Zixuan, Zhang Guangji, Fan Jia
Department of Neurology, The Second Hospital of Jilin University, Changchun 130022, China.
Beijing Institute of Biological Products Co., Ltd, Beijing 101149, China.
Cytokine. 2025 Aug;192:156973. doi: 10.1016/j.cyto.2025.156973. Epub 2025 May 30.
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.
