Cancer immunotherapies that harness the body's immune system to combat tumors have received extensive attention and become mainstream strategies for treating cancer. Despite promising results, some problems remain, such as the limited patient response rate and the emergence of severe immune‐related adverse effects. For most patients, the therapeutic efficacy of cancer immunotherapy is mainly limited by the immunosuppressive tumor microenvironment (TME). To overcome such obstacles in the TME, the immunomodulation of immunosuppressive factors and therapeutic immune cells (e.g., T cells and antigen‐presenting cells) should be carefully designed and evaluated. Nanoengineered synthetic immune niches have emerged as highly customizable platforms with a potent capability for reprogramming the immunosuppressive TME. Here, recent developments in nano‐biomaterials that are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy which are rationally designed to modulate the immunosuppressive TME in a spatiotemporal manner for enhanced cancer immunotherapy are highlighted.

The development of biomaterial-based immune niches that can modulate immunosuppressive factors in tumor microenvironment (TME) will be a key technology for improving current cancer immunotherapy. Here, implantable, engineered 3D porous scaffolds are designed to generate synergistic action between myeloid-derived suppressor cell (MDSC)-depleting agents, which can accommodate the establishment of a permissive immunogenic microenvironment to counteract tumor-induced immunosuppression, and cancer vaccines consisting of whole tumor lysates and nanogel-based adjuvants, which can generate tumor antigen-specific T cell responses. The local peritumoral implantation of the synthetic immune niche (termed immuneCare-DISC, iCD) as a postsurgical treatment in an advanced-stage primary 4T1 breast tumor model generates systemic antitumor immunity and prevents tumor recurrence at the surgical site as well as the migration of residual tumor cells into the lungs, resulting in 100% survival. These therapeutic outcomes are achieved through the inhibition of immunosuppressive MDSCs in tumors and spleens by releasing gemcitabine and recruitment/activation of dendritic cells, enhanced population of CD4 and CD8 T cells, and increased IFN-γ production by cancer vaccines from the iCD. This combined spatiotemporal modulation of tumor-derived immunosuppression and vaccine-induced immune stimulation through the iCD is expected to provide an immune niche for prevention of postoperative tumor recurrence and metastasis.

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.

The low response rate of current cancer immunotherapy suggests the presence of few antigen-specific T cells and a high number of immunosuppressive factors in tumor microenvironment (TME). Here, we develop a syringeable immunomodulatory multidomain nanogel (iGel) that overcomes the limitation by reprogramming of the pro-tumoral TME to antitumoral immune niches. Local and extended release of immunomodulatory drugs from iGel deplete immunosuppressive cells, while inducing immunogenic cell death and increased immunogenicity. When iGel is applied as a local postsurgical treatment, both systemic antitumor immunity and a memory T cell response are generated, and the recurrence and metastasis of tumors to lungs and other organs are significantly inhibited. Reshaping of the TME using iGel also reverts non-responding groups to checkpoint blockade therapies into responding groups. The iGel is expected as an immunotherapeutic platform that can reshape immunosuppressive TMEs and synergize cancer immunotherapy with checkpoint therapies, with minimized systemic toxicity.

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