Remodeling the tumor microenvironment to unlock CAR-T cell potential

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.