Degrade to Display: Coupling Checkpoint Degradation with Exogenous Antigen Presentation to Boost Antitumor Immunity

Membrane and extracellular targeted protein degradation (meTPD) has emerged as a revolutionary therapeutic modality against cancer, enabling the lysosomal clearance of traditionally undruggable oncogenic targets. However, the therapeutic potential of the current meTPD method is frequently compromised by its reliance on loss-of-function elimination in the face of tumor immunosuppression and low immunogenicity. This In Focus article highlights the development of the intratumoral vaccination chimera (iVAC), a "meTPD-Plus" platform that advances beyond target elimination to actively reprogram tumor immunogenicity. By coupling the degradation of PD-L1 with the cross-presentation of exogenous antigens within tumors, iVAC chemically reprograms cancer cells into pseudo antigen-presenting cell entities (pseudo-APCs) capable of engaging bystander memory T cells. This dual-mechanism approach simultaneously relieves checkpoint-mediated immune suppression and enhances tumor antigen presentation, thereby redirecting viral-specific bystander T cells toward tumor recognition and establishing durable, systemic antitumor immunity.