Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells

Plain language summary Chimeric antigen receptor T (CAR-T) cell therapy is emerging as a promising therapeutic approach for cancers in the blood. The success of CAR-T cells has also sparked interest in applying this strategy to solid tumors; however, attempts have been disappointing, with only a few patients achieving a partial response. The chemokine/chemokine receptor axis plays a key role in the growth and spread of tumors. Unfortunately, chemokines and chemokine receptors in immune cells and the environment surrounding the tumor do not always match, which results in inefficient immune cell trafficking and infiltration. Therefore, reversing the 'mismatch' of chemokines and chemokine receptors appears to be a promising method for potential treatment. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving CAR-T cell therapy by reversing this mismatch. Currently, the antitumor efficacy of chimeric antigen receptor T cells in solid tumors is modest. Both chemokines and their receptors play a key role in the proliferation of cancer cells, tumor angiogenesis, organ-selective metastasis and migration of immune cells to solid tumors. Unfortunately, frequent chemokine/chemokine receptor 'mismatch' between effector cells and the tumor microenvironment results in inefficient T-cell infiltration and antitumor efficacy. Thus, reversing the 'mismatch' of chemokines and chemokine receptors appears to be a promising method for promoting T-cell infiltration into the tumor and enhancing their antitumor efficacy. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving the effect of chimeric antigen receptor T cells by reversing the mismatch between chemokines and chemokine receptors.