Chimeric antigen receptor T (CAR-T) cell therapy has significantly advanced the treatment of blood cancers, but its effectiveness in solid tumors is still limited. The main obstacle is the tumor microenvironment (TME), which restricts CAR-T cell infiltration and activity.
A recent review published in Volume 138, Issue 19 of the Chinese Medical Journal on October 5, 2025, discusses new strategies to overcome these barriers. Solid tumors create several challenges for CAR-T cells, including abnormal blood vessels, a dense extracellular matrix, disrupted chemokine signaling, and immunosuppressive stromal cells. As a result, patients with solid tumors have circulating CAR-T levels that are five to ten times lower than those seen in blood cancer cases.
Researchers are addressing these issues by focusing on vascular normalization. For example, combining anti-VEGF drugs like bevacizumab with CAR-T therapy can remodel tumor blood vessels and improve T cell penetration. Preclinical studies show that blocking pathways such as PAK4 or altering endothelial cell metabolism can further enhance vascular function and boost the effectiveness of CAR-T cells.
Another approach involves modifying the chemokine system. By genetically engineering CAR-T cells to express specific chemokines or their receptors—such as CCL19, CXCL10, or CXCR6—scientists can guide T cells more efficiently toward tumor sites. A phase I clinical trial involving glypican-3-CAR-T cells co-expressing CCL19 and IL-7 demonstrated promising results in hepatocellular carcinoma patients.
Overcoming physical barriers is also important. Targeting fibroblast activation protein (FAP) on cancer-associated fibroblasts or using enzymes like hyaluronidase to break down the extracellular matrix helps improve CAR-T cell access to tumors. SynNotch CAR-T cells engineered to secrete matrix-degrading enzymes have shown increased antitumor activity in preclinical models.
Combining therapies can amplify outcomes: chemotherapy agents such as nab-paclitaxel disrupt tumor stroma; radiotherapy triggers inflammatory signals; and oncolytic viruses help remodel the TME. Additionally, local delivery methods—including intratumoral injection, biomaterial scaffolds, or oxygen-releasing systems—can increase CAR-T bioavailability while minimizing off-target effects.
Despite these advances, significant challenges remain before these approaches can be widely used in clinical practice. Translating results from preclinical models to humans remains difficult; optimizing CAR-T cell characteristics for use against solid tumors continues to be a focus; and scaling up biomaterial-based delivery systems poses logistical hurdles.
The review concludes: "The integration of immunology knowledge with genetic engineering technology and materials science will continue driving progress toward personalized solid tumor treatments."
