Harnessing cytokines to optimize chimeric antigen receptor-T cell therapy for gastric cancer: Current advances and innovative strategies

Enormous patients with gastric cancer (GC) are insensitive to chemotherapy and targeted therapy without the chance of radical surgery, so immunotherapy may supply a novel choice for them. Chimeric antigen receptor (CAR)-T cell therapy has the advantages of higher specificity, stronger lethality, and longer-lasting efficacy, and it has the potential for GC in the future. However, its application still faces numerous obstacles in terms of accuracy, efficacy, and safety. Cytokines can mediate the migration, proliferation, and survival of immune cells, regulate the duration and strength of immune responses, and are involved in the occurrence of severe side effects in CAR-T cell therapy. The expression levels of specific cytokines are associated with the genesis, invasion, metastasis, and prognosis of GC. Applications of cytokines and their receptors in CAR-T cell therapy have emerged, and various cytokines and their receptors have contributed to improving CAR-T cell anti-tumor capabilities. Large amounts of central cytokines in this therapy include chemokines, interleukins (ILs), transforming growth factor-β (TGF-β), and colony-stimulating factors (CSFs). Meanwhile, researchers have explored the combination therapy in treating GC, and several approaches applied to other malignancies can also be considered as references. Therefore, our review comprehensively outlines the biological functions and clinical significance of cytokines and summarizes current advances and innovative strategies for harnessing cytokines to optimize CAR-T cell therapy for GC.