Activation of Cascade‐Like Antitumor Immune Responses through In Situ Doxorubicin Stimulation and Blockade of Checkpoint Coinhibitory Receptor TIGIT

Abstract Although T cell centered immune checkpoint blockade (ICB) therapies have shown unprecedented success in various cancer types, only a minority of patients benefit from these treatments due to the lack of neoantigen burden and exhaustion of tumor‐infiltrating immune stimulating cells. Inspired by the crucial role of NK cell based immunity and potential immunostimulating effect of chemotherapeutic drugs, the therapeutic efficiency on tumor inhibition through combination of doxorubicin (DOX) and blockade of TIGIT (T‐cell Ig and ITIM domain), a coinhibitory receptor expressed by both NK and T cells, in a matrix metalloproteinase 2 (MMP‐2)‐degradable hydrogel is thoroughly evaluated in this study. Due to the distinct release kinetics from destructed framework of hydrogels, the differentially released DOX and anti‐TIGIT monoclonal antibody (aTIGIT) molecules can elicit immunogenic tumor microenvironment and reverse the exhaustion of NK and effector T cells to realize not only durable localized tumor inhibition but also systemic and long‐lasting immune memory responses. Thus, this work pioneers the union of chemotherapeutic drugs and NK cell centered ICB therapies for activating cascade‐like antitumor immune responses through eliciting immunogenic tumor microenvironment and boosting both innate and adaptive immunity.