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Recent developments in the fields of biomedical chemistry and immune bioengineering have enabled innovative therapeutic approaches that can enhance the efficacy, accuracy, and safety of cancer immunotherapy. Among the numerous strategies utilized in cancer immunotherapy, Toll-like receptor (TLR) agonist-based approaches have been studied for a long time since they trigger the innate immune system and generate antigen-specific T cell responses to fight against tumors. In addition to these immunostimulatory functions, TLR agonists also contribute to the reprogramming of immune suppressive tumor microenvironments. Although TLR agonists are now being intensively studied in clinical trials due to their substantial immunomodulatory properties, they still show a low therapeutic index. Nonspecific and random stimulation of various immune cells produces excess levels of proinflammatory cytokines, resulting in cytokine storms and chronic diseases. Therefore, the development of chemical strategies to enhance the therapeutic efficacy as well as the safety of TLR agonist-based immunotherapy is essential and in high demand.In this Account, we summarize and discuss recent developments in biomedical chemistry and bioengineering techniques for the immunomodulation of TLR agonists that have addressed the limitations in current cancer immunotherapy. Immunomodulation of TLR agonists can be classified into two different approaches: (1) molecular modulation via chemical structure modification and (2) macroscopic modulation via an engineered drug delivery system. In molecular modulation, based on prodrug and antedrug principles, activity is modulated (active or inactive) through immolative chemical linkers that can respond to extrinsic or intrinsic biological stimulation and the plasmatic environment, respectively. To increase the effectiveness of TLR agonists as immunostimulatory agents, researchers have conjugated TLR agonists with other immunotherapeutic moieties (antigen, antibody, other TLR agonist, etc.). For macroscopic modulation, bioengineering of delivery carriers differing in size or with albumin hitchhiking moieties has been utilized to increase the efficiency of the targeting of these carriers to secondary lymphoid organs (lymph nodes (LNs) and spleen). The conjugation of specific targeting ligands and incorporation of stimulus-triggering moieties can promote the delivery of TLR agonists into specific cells or intracellular compartments. Implantable porous scaffolds for specific immune cell recruitment and in situ depot-forming gel systems for controlled release of immunomodulatory drugs can increase the therapeutic efficacy of TLR agonists while reducing systemic toxicity. Taken together, these findings show that well-designed and precisely controlled chemical strategies for the immunomodulation of TLR agonists at both the molecular and macroscopic levels are expected to play key roles in improving the therapeutic efficacy of cancer immunotherapy while minimizing immune-related 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., The limited efficacy of current immunotherapy suggests low antigen-specific T cells and immunosuppressive factors in tumor microenvironment (TME). Here, the authors develop a syringeable immunomodulatory multi-domain nanogel that can reprogram the TME and induce enhanced cancer immunotherapy.