Breaking barriers: New strategies to boost CAR-T cell infiltration in solid tumors

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized hematologic cancer treatment, but its efficacy in solid tumors remains limited by poor infiltration into the complex tumor microenvironment (TME). A new review published in Volume 138, Issue 19 of the Chinese Medical Journal on October 05, 2025, outlines breakthrough strategies to address this critical bottleneck.

Solid tumors present multiple barriers: abnormal vasculature, dense extracellular matrix, disordered chemokine signals, and immunosuppressive stromal cells. These obstacles reduce CAR-T cell access to tumor cells, with circulating CAR-T levels in solid tumor patients 5–10 times lower than in hematologic cancer cases.

To tackle this, researchers are targeting vascular normalization. Anti-VEGF drugs like bevacizumab, when combined with CAR-T cells, remodel abnormal tumor blood vessels, improving T cell penetration. In preclinical models, inhibiting pathways like PAK4 or endothelial cell metabolism further enhances vascular function and CAR-T efficacy.

Modulating the chemokine system is another key strategy. Genetically engineering CAR-T cells to co-express chemokines (e.g., CCL19, CXCL10) or their receptors (e.g., CXCR6) creates targeted gradients, guiding T cells to tumors. A phase I trial of glypican-3-CAR-T cells co-expressing CCL19 and IL-7 showed promise in hepatocellular carcinoma.

Breaking physical barriers is also critical. Targeting fibroblast activation protein (FAP) on cancer-associated fibroblasts or using enzymes like hyaluronidase to degrade the extracellular matrix improves CAR-T infiltration. Preclinical studies with synNotch CAR-T cells secreting matrix-degrading enzymes have demonstrated enhanced antitumor activity.

Combination therapies amplify results: chemotherapy (e.g., nab-paclitaxel) disrupts stroma, radiotherapy triggers inflammatory signals, and oncolytic viruses remodel the TME. Local delivery methods—intratumoral injection, biomaterial scaffolds, or oxygen-releasing systems—boost CAR-T bioavailability while reducing off-target toxicity.

Despite progress, challenges persist: translating preclinical models to humans, optimizing CAR-T cell phenotypes for solid tumors, and scaling biomaterial-based delivery systems. The review emphasizes integrating immunology, genetic engineering, and materials science to advance personalized treatments.

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Reference
DOI: 10.1097/CM9.0000000000003803

About Dr. Yongzhan Nie from State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers
Dr. Yongzhan Nie
Affiliations:  State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Xi’an, Shaanxi 710032, China

Funding information
This work was financially supported by the National Natural Science Foundation of China (Nos. 82203042 and 82350122).