Work

Humanized and Charge‐Optimized CSPG4‐Specific CAR‐T Cells show Enhanced Efficacy against Head and Neck Squamous Cell Carcinoma

Year: 2026

Type: article

Abstract: ABSTRACT Major challenges of developing CAR‑T cell therapy for head and neck squamous cell carcinoma (HNSCC) include identifying a robust tumor antigen and a suitable CAR design. Here, we validate chondroitin sulfate proteoglycan 4 (CSPG4) as a highly expressed, prognostic antigen in HPV‑negative HNSCC that drives tumor proliferation. By grafting the murine single‐chain variable fragment (scFv) 763.74 complementarity determining regions (CDRs) onto a human antibody framework engineered to minimize surface positive‑charge patches and immunogenic epitopes, we generated humanized CSPG4 (CSPG4 Hu ) CAR‑T cells with reduced tonic signaling and alleviated exhaustion. Transcriptomic and metabolic profiling reveal that this biophysical refinement reprograms CAR‐T cells away from a glycolytic, terminal exhaustion state toward a PI3K/Akt‐driven stem‐like state. Consequently, CSPG4 Hu CAR‐T cells demonstrate superior persistence and potent antitumor efficacy across systemic xenograft and patient‐derived xenograft models. Our study establishes a rational engineering framework that links biophysical CAR design to transcriptomic and metabolic rejuvenation, offering a promising therapeutic candidate for advanced HNSCC.

Source: Advanced Science

DOI: 10.1002/advs.202519746