ARV-825

Personalized in situ tumor vaccines (ISTVs) have emerged as a promising approach to activating potent T cell-mediated anticancer immunity through the induction of immunogenic cell death (ICD) and the subsequent release of tumor-associated antigens (TAAs). However, their efficacy is limited by non-specific ICD, inadequate TAAs cross-presentation, and the stubborn immunosuppressive tumor microenvironment (TME). Here, we develop a novel ISTV platform (SOM-ZIF-8@Mn/ARV) integrating a specific ICD inducer (ARV-825), and a multifunctional antigen catcher (SOM-ZIF-8@Mn) to boost antitumor immunity. ARV-825, as a protein targeted degradation chimera (PROTAC), selectively degrades bromodomain-containing protein4 (BRD4) to induce potent ICD, while the produced TAAs are effectively captured by SOM-ZIF-8@Mn to in situ generate a vaccination effect. Leveraging its unique hierarchical porous structure and rough surface, SOM-ZIF-8@Mn exhibits enhanced antigen capture efficiency, enabling the adsorption of both soluble TAAs and tumor cell fragments. Additionally, Mn²⁺ released from SOM-ZIF-8@Mn under TME conditions activates the STING pathway, promotes dendritic cell maturation and antigen cross-presentation, thereby activating CD8⁺ T cells for efficient tumor-specific immunity. Furthermore, the platform reprograms tumor-associated macrophages into pro-inflammatory M1 phenotypes, alleviating TME immunosuppression. This ISTV platform triggers robust antitumor immunity and achieves significant tumor growth inhibition when combined with αPD-1 blockade. The SOM-ZIF-8@Mn/ARV platform represents a powerful and effective advancement in improving the antitumor immune efficiency of ISTVs, offering a straightforward approach to the challenges faced in tumor immunotherapy.

Targeted protein degradation via bifunctional molecules represents a promising therapeutic strategy, where successful degradation requires efficient ternary complex formation. This study establishes an integrated framework for reliable kinetic characterization of ternary complexes by combining theoretical modeling with experimental validation. We demonstrate that binary binding parameters can effectively guide experimental design, while proper component immobilization and the use of calibrated concentrations of pre-formed binary complexes ensure measurement accuracy. Application to the CRBN/ARV-825/BRD4 system reveals strong positive cooperativity (α = 175), which correlates with exceptional degradation potency. Our approach provides a systematic methodology for quantifying ternary complex kinetics and offers a robust platform for rational degrader optimization through kinetic-guided design.