Nanodecoys Unleash Immune Potential To Reprogram Robust Anti-Tumor Defense

The deficiency of robust cytotoxic T lymphocyte (CTL) response and sustained anti-tumor microenvironment represents persistent dilemmas during tumor immunotherapy. Hence, rebooting the immune system to overcome existing intractable obstacles is pivotal. We developed a strategy of strengthening host and weakening tumor by constructing Nanodecoys to synergistically achieve tumor microenvironment immunosuppression reversal and induce antigen-specific immune response. Nanodecoys were fabricated by integration of immunocompetent membrane with LPS/Decitabine-loading nanoparticles. The physicochemical and biological properties of Nanodecoys were characterized and detected in vitro. Primary, recurrent, and metastasis models of melanoma were constructed to investigate the inhibitory effect of Nanodecoys on tumor growth. RNA-seq analysis was applied to evaluate the effect on immune revitalization and tumor microenvironment. Nanodecoys exhibited the excellent colloidal stability and biocompatibility. Nanodecoys blocked PD-L1/CD47 checkpoints and induced tumor-intrinsic pyroptotic cascades by LPS/Decitabine-mediated GSDMD cleavage in vitro. The released tumor lysates triggered the specific immune activation. In the tumor-bearing mice, infused Nanodecoys were enriched in lymph nodes and tumor foci, costimulated the innate immunity and induced tumor pyroptosis. Nanodecoys elicited a tumor suppressive efficacy greater than 90% in tumor growth, recurrence, and metastasis. The pyroptosis process primed potent CTL activation and specific memory T cells formation, establishing a long-term immune defense. Nanodecoys reprogram and enhance the efficacy of tumor immunotherapy through a two-pronged approach of immunosuppression reversal and pyroptosis induction, highlighting the potential of Nanodecoys as a self-amplifying anti-tumor immune circuit.