Abstract
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.
Highlights
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)
The immunomodulatory multidomain nanogel can be formed by electrostatic interactions with negatively charged non-concentric multi-nanodomain vesicles (MNDVs) and positively charged nanoliposomes, which were loaded with immunomodulatory drugs, and the gel structure can be temporally disassembled by shear-force during the syringe injection and assembled again after the shear-force is removed at the treatment site (Fig. 1b)
MNDVs were further developed as a syringeable gel that can fill the irregular space of a tumor surgical bed without dead volume (Fig. 1b), prolong the residence time of MNDVs, and extend the release of immunomodulatory drugs in the surgical area without moving into other sites
Summary
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). Local delivery can increase the bioavailability and allow multiple combination therapies of immunostimulatory drugs, while preventing significant systemic exposure and off-target toxicities[32,33,34] To address this issue, we hypothesized that the local synthetic immune niches based on nanopharmaceutical formulations of multiple immunomodulatory drugs for the modulating key components of the TME could be used to overcome the abovementioned limitations of current immunotherapy. We suggest a syringeable synthetic immune niche based on nanoliposome-bridged non-concentric multi-nanodomain vesicle gels that can modulate tumor-induced immunosuppressive TMEs in a spatiotemporal manner, enhance antitumor immune priming as an in situ cancer vaccine, and increase the therapeutic efficacy of combination cancer therapies with checkpoint therapies while minimizing treatment-associated adverse effects (Fig. 1a). Local reprogramming of the TME by iGel leads to systemic antitumor immunity and synergizes the therapeutic efficacy of immune checkpoint inhibitors, resulting in the prevention of tumor recurrence and metastasis (Fig. 1a)
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