Chemokines as regulators of CAR-T cell trafficking, function, and context-dependent tumor cell death

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its efficacy in solid tumors remains limited by inefficient trafficking, suppressive myeloid and regulatory T-cell populations, and metabolic stress. These barriers contribute to incomplete tumor cell killing and loss of CAR-T cell function. Chemokines are usually viewed as migratory guides, but in solid tumors they also orchestrate immune cell positioning and inflammatory state. In this review, we discuss how chemokine gradients form inflammatory niches and control CAR-T-cell recruitment, intratumoral distribution, retention, and egress. We also examine how chemokine programs interact with cytokine signaling and regulated tumor cell death to shape local and potentially tissue-wide antitumor immunity, including through the release of damage-associated molecular patterns (DAMPs). Finally, we outline translational strategies that include engineered chemokines and matched chemokine receptor programs to enhance the efficacy of chemokine/cytokine-armored CAR-T cells, and related combination therapies.