Chimeric antigen receptors (CARs) are synthetic receptors that can translate extracellular binding of tumor-associated antigens to intracellular T-cell signaling. T cells engineered to express CAR molecules can recognize antigens in a major histocompatibility complex-independent manner, resulting in antigen-specific T-cell activation and cytotoxicity. In general, CARs are composed of an extracellular antigen-recognition domain, hinge and transmembrane domains, and intracellular signaling domains, and the modularity of the fusion protein has enabled calibration of each component to improve the antitumor efficacy of CAR-T cells [1]. For example, the earliest ‘first-generation’ CARs incorporated only the CD3ζ chain as their intracellular T-cell signaling domain 2, 3. In subsequent development, second- and third-generation CARs were constructed with one or two costimulatory domains, most commonly CD28 or 4-1BB, that provide additional signals to bolster antitumor cytotoxicity, cytokine production, and persistence of CAR-T cells 4, 5. Notably, CAR-T cells have shown remarkable therapeutic efficacy against advanced hematological malignancies, leading to their US Food and Drug Administration approval for the treatment of relapsed/refractory B-cell leukemia, lymphoma, and multiple myeloma 6, 7, 8.

Despite the promising clinical outlook of CAR-T cells in liquid tumors, their efficacy against solid tumors has been severely hindered by multiple challenges, including antigen heterogeneity and antigen escape, systemic as well as on-target, off-tumor toxicities, and immunosuppressive tumor microenvironments (TMEs) that render CAR-T cells dysfunctional. Each of these areas have been extensively reviewed elsewhere 9, 10, 11, 12, 13, 14, 15. Here, we focus on the challenge of CAR-T cells trafficking to and infiltrating solid tumors.

For CAR-T cells to exert antitumor efficacy, they must first traffic to the tumor site, a prerequisite that is not automatically achieved for systemically administered cell products. Chemokines and their cognate G-protein-coupled receptors comprise a broad network of immune-cell recruitment signals that plays a critical role in directing CAR-T cells to solid tumors. However, the chemokine network is often dysregulated during oncogenesis, impeding leukocyte homing and tissue infiltration while enabling tumor immune escape and immunosuppression (Figure 1) 16, 17, 18. Here, we discuss recent chemokine-based engineering strategies and locoregional delivery methods to augment CAR-T-cell localization at solid-tumor sites to improve therapeutic efficacy and safety.