Many solid tumours are described as immune-cold because they both express checkpoint proteins such as PD-L1 and present too few antigens for T cells to recognise, a combination that limits response to checkpoint blockade. A team led from the College of Chemistry and Molecular Engineering at Peking University designed an agent that addresses both problems at once by reprogramming the tumour cell rather than stimulating the immune cell.
The construct, called iVAC, enters tumour cells through a covalent nanobody-based targeting module and engages the lysosomal degradation pathway. That pathway degrades PD-L1, removing the inhibitory signal, and simultaneously processes engineered antigenic peptides carried by the construct for display on MHC molecules at the cell surface. The tumour cell is thereby converted into an antigen-presenting unit advertising peptides chosen by the experimenter.
The design proved sensitive to details that are easy to overlook. The amino acid sequences flanking the antigenic peptides were essential for stable and effective presentation, since the peptides must survive processing and load correctly onto MHC. Across tumour cell lines, mouse models and patient-derived organoids, iVAC triggered robust T-cell activation and produced more durable antitumour responses than conventional checkpoint blockade. The work was published in Nature.
The approach builds on the group's earlier membrane protein degradation platforms, which is why the targeted-degradation machinery is mature enough to carry a second payload. Modularity is the strategic claim: because the targeting module and the antigenic cargo are separable, the construct could in principle be adapted rapidly to different tumour antigens, which is the central requirement for personalised cancer vaccines.