A Synergistic Chemoimmunotherapy System Leveraging PD‐L1 Blocking and Bioorthogonal Prodrug Activation

Abstract

AbstractNovel strategies to facilitate tumor‐specific drug delivery and restore immune attacks remain challenging in overcoming the current limitations of chemoimmunotherapy. An antitumor chemoimmunotherapy system comprising bioorthogonal reaction‐ready group tetrazine (TZ) modified with an anti‐PD‐L1 antibody (αPD‐L1TZ) and TZ‐activatable prodrug vinyl ether‐doxorubicin (DOX‐VE) for self‐reinforced anti‐tumor chemoimmunotherapy is proposed. The αPD‐L1TZ effectively disrupts the PD‐L1/PD‐1 interaction and activates the DOX prodrug in situ through the bioorthogonal click reaction of TZ and VE. Conversely, the activated DOX upregulates PD‐L1 on the surface of tumor cells, facilitating tumor accumulation of αPD‐L1TZ and enhancing DOX‐VE activation. Furthermore, the activated DOX‐induced immunogenic cell death of tumor cells, substantially improving the response efficiency of αPD‐L1 in an immune‐suppressive tumor microenvironment. Thus, PD‐L1 blocking and bioorthogonal in situ prodrug activation synergistically enhance the antitumor efficacy of the chemoimmunotherapy system. Therefore, the system significantly enhances αPD‐L1 tumor accumulation and prodrug activation and induces a robust immunological memory effect to prevent tumor recurrence and metastasis. Thus, a feasible chemoimmunotherapy combination regimen is presented.