Tumor cell membrane remodeling with universal ligand for CAR-T cells to inhibit solid tumors

Heterogeneity is a major obstacle to the success of CAR-T therapy in treating solid tumors. The complex tumor microenvironment and varying phenotypes of tumor cells might result in antigen escape, drug resistance, and tumor recurrence. To address this issue, we proposed to use lipid-modified fluorescein isothiocyanate (Lip-FITC) as an artificial ligand to normalize the phenotypes of solid tumor cells. In murine cutaneous melanoma and colon adenocarcinoma that prefer to utilize exogenous long-chain fatty acids, we observed much more uptake of Lip-FITC and significantly increased FITC fluorescence on tumor cell membranes than normal cells. This specific exogenous labeling with FITC enhanced the recognition and selectivity of CART cells in solid tumors, bypassing the limitations derived from antigen expression differences in adoptive cell therapies. Lipid metabolism analysis and in vitro experiments demonstrated the sufficient uptake of long-chain fatty acid (LCFAs)-modified Lip-FITC by solid tumor cells, as well as satisfactory ligand assembly on cell membranes. In solid tumor model, the treatment induced the recognition and initiation of CART cells and successfully suppressed tumor progression through T-cell immunity.