Common gamma chain cytokines-driven optimization of chimeric antigen receptor T cells: Mechanistic insights and future directions

Abstract

Malignant tumors represent a major threat to human life and health, posing persistent challenges in medical research. While chimeric antigen receptor T (CAR-T) cell therapy has demonstrated breakthrough efficacy in hematological malignancies such as leukemia and lymphoma, its application in solid tumors, including hepatocellular carcinoma, lung cancer, and pancreatic cancer, remains constrained by multiple bottlenecks. These limitations encompass the immunosuppressive tumor microenvironment, insufficient in vivo persistence of CAR-T cells, long-term treatment-induced exhaustion, and off-target toxicity. The interleukin (IL)-2 family cytokines, IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, also known as gamma chain (γc) cytokines, share the γc (CD132)-Janus kinase 1/3-signal transducer and activator of transcription signaling axis. These cytokines precisely regulate the survival, proliferation, and functional differentiation of immune cells, including T cells and natural killer cells. In CAR-T immunotherapy, γc cytokines are applied in four core scenarios: Facilitating efficient in vitro CAR-T cell expansion to meet therapeutic dosing requirements; enhancing in vivo persistence to extend the therapeutic window; reinforcing effector functions to counteract tumor microenvironment-mediated suppression; and enabling precise cytokine release to mitigate toxicity risks. Technological strategies have evolved from early recombinant protein administration (in vitro and in vivo) to second-generation “armored” CAR-T cells engineered for autocrine cytokine secretion and further to third-generation programmable cytokine circuits using synthetic biology for spatiotemporal control. This review systematically summarizes the mechanistic roles, research progress, and technological evolution of γc cytokines in optimizing CAR-T cell function. It critically analyzes the advantages and limitations of different application strategies and explores their potential to overcome solid tumor treatment bottlenecks while improving CAR-T therapy safety and efficacy. These insights aim to inform basic research and clinical translation in this field.

Keywords: Chimeric antigen receptor T therapy; Gamma chain cytokines; Solid tumors; Tumor microenvironment; Clinical translation

Core Tip: Gamma chain (γc) cytokines [interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, IL-21], signaling through the shared γc-Janus kinase 1/3-signal transducer and activator of transcription pathway, critically enhance chimeric antigen receptor T (CAR-T) cell efficacy by modulating proliferation, stemness maintenance, metabolic fitness, and resilience to the immunosuppressive tumor microenvironment. Strategic application, via cytokine selection, spatiotemporal delivery, multi-factor synergy, or genetic engineering (e.g., cytokine-secreting/γc receptor-chimeric CAR-Ts), overcomes key bottlenecks in solid tumor treatment. Clinical breakthroughs, such as IL-15-armored glypican-3 CAR-T and IL-7/C-C motif chemokine ligand 19-co-expressing 7 × 19 CAR-T, demonstrate improved persistence and objective responses, advancing CAR-T therapy from hematologic malignancies toward controllable solid tumor interventions.