Bright future or blind alley? CAR-T cell therapy for solid tumors

Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a key-and-lock relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.

Automated summary

Chimeric antigen receptor (CAR) T cells therapy has shown success in hematological malignancies but faces challenges in solid tumors due to lack of suitable target antigens, limited trafficking and survival in the tumor microenvironment, and potential toxicities. This review explores the development of CARs, clinical trials in solid tumors, and strategies to improve target specificity and minimize off-target effects. Additionally, innovations in engineering CARs to overcome inhibitory signaling and enhance CAR T cell functions in the complex tumor microenvironment are discussed.