Intratumoural vaccination via checkpoint degradation-coupled antigen presentation
Article Date: 07 January 2026
Article URL: https://www.nature.com/articles/s41586-025-09903-1
Article Image: (none provided)
Summary
This Nature paper presents iVAC — an intratumoural vaccination strategy that couples targeted PD-L1 degradation with local antigen delivery to convert tumour cells into antigen-presenting, pro-inflammatory cells. Using proximity-reactive chemistry (FnFSYs) and engineered antibody constructs (GlueBody/iVAC), the authors trigger PD-L1 removal and deliver peptide epitopes into tumours so those cells cross-present antigen on MHC-I, recruit and activate CD8+ T cells (including pre-existing virus-specific memory T cells), and cause tumour control in mouse models and patient-derived tumour-like clusters.
Key Points
- iVAC combines targeted PD-L1 degradation with intratumoural antigen delivery to force tumour cells into an APC-like state.
- Proximity-reactive fluorosulfuryl tyrosine (FnFSY) chemistry and an engineered tRNA synthetase enable site-specific covalent crosslinking to PD-L1, accelerating its degradation.
- Degraded PD-L1 plus delivered peptide (viral or tumour antigens) leads to lysosomal escape of antigen (perforin-2 dependent) and cross-presentation on MHC-I.
- APC-like tumour cells stimulate CD8+ T cell activation and expansion, restoring anti-tumour T cell activity in PD-L1 humanised mouse models and reducing tumour growth.
- Ex vivo patient-derived tumour-like clusters (PTCs) show iVAC responses that correlate with tumour PD-L1 levels, indicating translational potential and a biomarker for response.
- Biodistribution and tolerability studies (intratumoural dosing) show local retention and acceptable safety in mouse models.
- Data and raw sequencing/proteomics datasets are deposited (CRA031318; IPX0013811000) and available with the Article and Supplementary Information.
Content summary
The team engineered proximity-reactive amino acids (FnFSYs) and an optimised aminoacyl-tRNA synthetase to incorporate these into antibody-like constructs (GlueBody variants). These constructs bind PD-L1 and use a chemistry-enabled crosslink to promote rapid PD-L1 degradation in tumour cells while delivering peptide epitopes (for example, OVA or viral peptides).
Once inside tumour cells, the delivered antigen can escape lysosomes (a process shown to depend on perforin-2) and be cross-presented on MHC class I, effectively turning tumour cells into antigen-presenting cells (APC-like). This local conversion increases inflammatory signalling (IFN-γ, STING pathways) and recruits/activates CD8+ T cells, including memory T cells specific for common viral epitopes, redirecting them to attack the tumour.
Preclinical evaluation in PD-L1 humanised C57BL/6J mouse models demonstrated PD-L1 degradation, increased tumour infiltration by T cells and dendritic markers, and tumour control after intratumoural iVAC administrations. Ex vivo testing on patient-derived tumour-like clusters (PTCs) showed that tumours with higher PD-L1 percentage tended to respond better, suggesting a practical stratification marker for potential clinical application.
Context and relevance
Why it matters: resistance to systemic immune-checkpoint blockade is a major clinical problem. This work fuses targeted protein degradation, bioorthogonal chemistry and intratumoural vaccination to bypass systemic resistance mechanisms by locally removing PD-L1 and promoting antigen presentation in situ. It sits at the intersection of several active trends: intratumoural immunotherapies, targeted extracellular degraders (LYTAC/PROTAC-like concepts), and strategies harnessing pre-existing virus-specific T cell repertoires for cancer therapy.
Punchy note from the authors’ perspective: this is a conceptually new way to make tumours present antigens and attract T cells without relying solely on systemic checkpoint blockade — that could be a big step toward safer, more localised immunotherapy approaches and personalised intratumoural vaccines.
Why should I read this
Short version: if you follow cancer immunotherapy, this paper is a neat bit of chemical biology + immunology that actually does something useful — it turns tumours into their own vaccine factories and gets T cells doing the job. Saves you digging through dense methods: they engineered the chemistry, showed PD-L1 gets knocked down, antigen gets shown on MHC-I, and T cells respond — even in patient-derived samples. If you want to know how targeted degradation can be married to vaccination inside the tumour, read this.