CELL INTELLIGENCE · 肿瘤细胞治疗研究

Tumors remodel the extracellular matrix (ECM) and glycosylation, yielding epitopes with restricted or limited detectability in normal adult tissues. In this study, we evaluated the O-glycosylated type III connecting segment domain of fibronectin (Tn-FN) as a chimeric antigen receptor (CAR) T-cell target. FDC6-BB CAR T cells recognizing Tn-FN were benchmarked against extra domain B-FN-targeted L19-BB and Tn-MUC1-targeted 5E5-BB . FDC6-BB mediated robust, antigen-dependent activation and cytotoxicity, outperforming L19-BB and matching 5E5-BB in vitro and in NOD/SCID gamma xenografts of prostate cancer. FDC6-BB and 5E5-BB CAR T cells achieved durable tumor control with increased intratumoral CD3+ infiltration and reduced tumor-collagen overlap. Cytotoxicity required an intact tumor IFN receptor 1 (IFN R1); L19-BB further depended on Fas, whereas FDC6-BB and 5E5-BB were less Fas-dependent. Tumoral Toll-like receptor (TLR) 2/6 or TLR4 agonism restored FDC6-BB killing of IFN R1-deficient targets and induced broad inflammatory and stress-response programs. Pharmacologic perturbation implicated caspase-dependent mechanisms and a contribution from inflammasome-linked signaling, whereas ferroptosis blockade did not abrogate restored killing. These findings establish Tn-FN as a glycoform-restricted, ECM-derived CAR target and show that innate agonists can reprogram tumor state to overcome resistance from impaired IFN signaling.