Polymerization of L‐Arginine into Nanomicelles for Immunometabolic Engineering of Adoptive Macrophages in Solid Tumor Therapy

A strategy of regulating immunometabolism of adoptive macrophages in vivo is reported by synthesizing L-arginine-based polymeric nanomicelles and integrating them within macrophages (PLANO@Mø). PLANO@Mø could display augmented tumor-killing potential and induce robust immune response. In the 4T1 murine model, PLANO@Mø showed an obvious inhibition effect on tumor progression.

Abstract

The therapeutic efficacy of adoptive cell therapy is highly dependent on the status and function of the infused cells. However, insufficient nutrient availability within the immunosuppressive tumor microenvironment (TME) often impedes these cells from fully exerting their cytotoxic potential against solid tumors. Here, we present a strategy of integrating adoptively transferred macrophages with intracellular nutrient depots composed of L-arginine-based nanomicelles to provide a sustainable supply of essential metabolite and optimize the cellular activity in the nutrient-deprived TME. Also, the nanomicelles were coated with bacterial outer membrane vesicles to endow them with immunomodulatory capability, which could activate macrophages toward anti-tumor phenotypes and resist immune suppression. We showed that our approach significantly strengthened the tumor-killing potential of macrophages, induced robust immune responses, and effectively inhibited solid tumor growth compared to the administration of an equal dose of macrophages without immunometabolic modulation. This work provides a method for orchestrating the behavior of transferred cells in vivo, offering a promising strategy to better unleash the potential of adoptive cell therapies against solid tumors.

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