A Designer Scaffold with Immune Nanoconverters for Reverting Immunosuppression and Enhancing Immune Checkpoint Blockade Therapy

Abstract Current cancer immunotherapy based on immune checkpoint blockade (ICB) still suffers from low response rate and systemic toxicity. To overcome the limitation, a novel therapeutic platform that can revert nonimmunogenic tumors into immunogenic phenotype is highly required. Herein, a designer scaffold loaded with both immune nanoconverters encapsulated with resiquimod (iNCVs (R848)) and doxorubicin, which provides the polarization of immunosuppressive tumor‐associated macrophages (TAMs) and myeloid‐derived suppressor cells (MDSCs) into tumoricidal antigen‐presenting cells (APCs), rather than depleting them, as well as in situ vaccination that can be generated in vivo without the need to previously analyze and sequence tumor antigens to favor neoantigen‐specific T cell responses is suggested. Local and sustained release of iNCVs (R848) and doxorubicin from the designer scaffold not only reduces the frequency of immunosuppressive cells in tumors but also increases systemic antitumor immune response, while minimizing systemic toxicity. Reshaping the tumor microenivronment (TME) using the designer‐scaffold‐induced synergistic antitumor immunity with ICB effects and long‐term central and effector memory T cell responses, results in the prevention of postsurgical tumor recurrence and metastasis. The spatiotemporal modulation of TMEs through designer scaffolds is expected to be a strategy to overcome the limitations and improve the therapeutic efficacy of current immunotherapies with minimized systemic toxicity.