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Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

ABSTRACT: The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy. Herein, we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses. Briefly, a microbiotic nanomedicine, designated as Cu₂O@ΔSt, has been constructed by conjugating PEGylated Cu₂O nanoparticles on the surface of an engineered Salmonella typhimurium strain (ΔSt). Owing to the natural hypoxia tropism of ΔSt, Cu₂O@ΔSt could selectively colonize hypoxic solid tumors, thus minimizing the adverse effects of the bacteria on normal tissues. Upon bacterial metabolism within the tumor, Cu₂O@ΔSt generates H₂S gas and other acidic substances in the tumor microenvironment (TME), which will in situ trigger the sulfidation of Cu₂O to form CuS facilitating tumor-specific photothermal therapy (PTT) under local NIR laser irradiation on the one hand. Meanwhile, the dissolved Cu⁺ ions from Cu₂O into the acidified TME enables the nanocatalytic tumor therapy by catalyzing the Fenton-like reaction of decomposing endogenous H₂O₂ into cytotoxic hydroxyl radicals (·OH) on the other hand. Such a bacterial metabolism-triggered PTT-enhanced nanocatalytic treatment could effectively destroy tumor cells and induce a massive release of tumor antigens and damage-associated molecular patterns, thereby sensitizing tumors to checkpoint blockade (ICB) therapy. The combined nanocatalytic and ICB therapy results in the much-inhibited growth of distant and metastatic tumors, and more importantly, induces a powerful immunological memory effect after the primary tumor ablation.

SUBMITTER: Wu W

PROVIDER: S-EPMC9652197 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

Wu Wencheng W Pu Yinying Y Gao Shuang S Shen Yucui Y Zhou Min M Yao Heliang H Shi Jianlin J

Nano-micro letters 20221111 1

The low immunogenicity of tumors remains one of the major limitations of cancer immunotherapy. Herein, we report a bacterial metabolism-initiated and photothermal-enhanced nanocatalytic therapy strategy to completely eradicate primary tumor by triggering highly effective antitumor immune responses. Briefly, a microbiotic nanomedicine, designated as Cu<sub>2</sub>O@ΔSt, has been constructed by conjugating PEGylated Cu<sub>2</sub>O nanoparticles on the surface of an engineered Salmonella typhimuri ...[more]

PMID: 36367591

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Project description:Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.

Dataset Information

Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

Publications

Bacterial Metabolism-Initiated Nanocatalytic Tumor Immunotherapy.

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