Targeted degradation of CD24 by a transferrin receptor-engaging bispecific degrader enhances antitumor immunity.

Targeted degradation of extracellular and membrane-associated proteins has emerged as a promising therapeutic modality. Here, we developed CD24-H7, a novel bispecific degrader that engages the transferrin receptor (TFRC) to mediate lysosomal degradation of CD24-an immunosuppressive protein commonly overexpressed in tumors. CD24-H7 consists of a TFRC-binding scFv and a CD24-specific scFv linked by a cathepsin-cleavable spacer, facilitating efficient internalization, lysosomal delivery, and subsequent recycling of TFRC. In vitro and in vivo experiments revealed potent and specific degradation of CD24, leading to marked suppression of tumor growth and enhanced antitumor immunity in humanized mouse glioblastoma (GBM) models. The degrader also exhibited a favorable safety profile with minimal on-target off-tumor toxicity. Moreover, combining CD24-H7 with anti-PD-1 antibodies synergistically promoted intratumoral CD8 T cell infiltration and cytotoxicity while attenuating T cell exhaustion, resulting in significantly enhanced antitumor efficacy compared to monotherapy. These findings underscore the therapeutic potential of TFRC-recruiting degraders for selective targeting of membrane proteins and provide a compelling combinatorial approach to overcome immune evasion in oncology.