Chimeric antigen receptor T (CAR-T) cells represent a novel immunotherapeutic approach that enables cytotoxic T cells to directly recognize tumor antigens and subsequently kill target tumor cells. For antigen recognition, the variable regions from the heavy and light chains of a monoclonal antibody are linked with a short amino acid chain called a linker to form a single-chain variable region fragment (scFv). To facilitate cell activation, the scFv is fused with the immunoreceptor tyrosine activation motif (ITAM) domain from an immune receptor (in most cases, the CD3ζ chain) to form a chimeric molecule designated the CAR. As T cells require a second signal for optimal activation, the intracellular domain from T cell costimulatory molecules such as CD28 or 4-1BB is frequently incorporated, resulting in second-generation CARs.

CAR-T cell therapies against blood cancers, such as anti-CD19 CAR-T cells and anti-BCMA CAR-T cells, have demonstrated remarkable efficacy in clinical trials [[1], [2], [3]]. In addition, some recent clinical trials, such as Claudin18.2-specific CAR-T cells for gastrointestinal cancers [4] and GD2-CAR-T cells for high-risk neuroblastoma [5], have shown promising results. However, most of the other attempts to develop CAR-T cells against a broader range of cancers have not yet achieved comparable success, particularly in the case of solid tumors (Table 1). For example, in a glioma clinical trial targeting EGFRvIII, patients did not respond to CAR-T cell therapy [6]. In addition, some clinical trials, such as CAR-T cells targeting PD-L1, HER2, and CEACAM5 in solid tumors, were halted due to severe on-target off-tumor adverse effects [[7], [8], [9]]. Furthermore, most of the early clinical trials with CAR-T cells targeting mesothelin, a popular target in solid tumors including malignant pleural mesothelioma (MPM), ovarian cancer and pancreatic adenocarcinoma, resulted in unsatisfactory outcomes [10,11]. In sharp contrast, anti-mesothelin CAR-T cells eradicated large, established human ovarian cancer cell xenografts in NSG mice [12], suggesting that there may be human-specific hurdles to CAR-T cell therapy for solid tumors. These observations suggest that there are critical differences in the environment of action of CAR-T cell therapy between blood cancers and solid tumors and that considerable modifications to CAR-T cell therapy are needed to overcome insufficient efficacy and adverse effects.

The primary difference between solid tumors and blood cancers may be the tumor microenvironment. Solid tumors may create an environment that inhibits CAR-T cell function by modulating the host immune system. Recently, a comprehensive review of CAR-T cell therapy for solid tumors was published, focusing primarily on clinical progress and technological developments [13]. In contrast, this review aims to approach the topic from a mechanistic and problem-oriented perspective, highlighting key biological and immunological barriers and discussing potential strategies to overcome them based on recent preclinical and translational findings.