Recent advances in chemokine-directed strategies to improve CAR-T cell infiltration into solid tumors

Limited infiltration of CAR-T cells into solid tumors remains a major obstacle to their therapeutic efficacy. Strategies to enhance tumor penetration-such as stromal matrix degradation, induction of tissue-resident memory CAR-T cells, and intratumoral delivery-have shown potential, yet achieving CAR-T cells infiltration comparable to that of conventional T cells may offer the greatest promise. Chemokine-receptor interactions are central to this process, but their expression is often dysregulated within tumors, leading to mismatched signaling and impaired CAR-T trafficking. Recent studies targeting chemokine and receptor pathways in either CAR-T cells or the tumor microenvironment have demonstrated encouraging results in preclinical and early clinical settings. Although existing reviews touch on these approaches but often do briefly or incompletely as part of broader discussions of CAR-T therapy. Here, we provided a specifically focused review about chemokine/receptor modulation to enhance CAR-T cells infiltration and antitumor activity, structured according to chemokine classification based on structural characteristics. Multiple chemokine-receptor axes could improve CAR-T cell infiltration and anti-tumor activity. The strategies to establish chemokine-receptor gradient include engineering chemokines or receptors directly into CAR constructs, modulating chemokines or receptors expression through culture additives, co-infusing chemokine-secreting antigen-presenting cells, stimulating chemokines production via physical or pharmacologic agents, and delivering directly chemokines or receptors into tumor microenvironment using oncolytic viruses, etc. This review outlines key advances and offers insight into the rational design of next-generation CAR-T therapies targeting solid tumors.