The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases

Marullo, Rossella; Castro, Miriam Susana; Calvo-Vidal, M. Nieves; Revuelta, María V.; Krumsiek, Jan; Cho, Andrew; Morgado, Pablo Cresta; Shen, Yang; Medina, Vanina Araceli; Roth, Berta; Bonomi, Marcelo; Keshari, Kayvan R.; Mittal, Vivek; Navigante, Alfredo; Cerchietti, Leandro

doi:10.1126/sciadv.abg1964

Cited by 25 publications

(14 citation statements)

References 60 publications

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“…Recently, another opposing strategy for radiosensitization in solid tumors was reported. Rossella Marullo et al demonstrated that administration of oral L-arginine induced radiosensitization and local control in patients who underwent standard radiation therapy 112 , which is associated with increased DNA damage via nitric oxide (NO)-mediated metabolic suppression 112 . It is worth mentioning that NO plays a dual role in tumor cells.…”

Section: Amino Acid Metabolism and Cancer Radioresistancementioning

confidence: 99%

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Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

Yu¹,

Yu²,

Ge³

et al. 2023

Int. J. Biol. Sci.

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Currently, cancer treatment mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy, of which radiotherapy is one of the major pillars. However, the occurrence of radioresistance largely limits its therapeutic effect. Metabolic reprogramming is an important hallmark in cancer progression and treatment resistance. In radiotherapy, DNA breakage is the major mechanism of cell damage, and in turn, cancer cells are prone to increase the metabolic flux of glucose, glutamine, serine, arginine, fatty acids etc., thus providing sufficient substrates and energy for DNA damage repair. Therefore, studying the linkage between metabolic reprogramming and cancer radioresistance may provide new ideas for improving the efficacy of tumor therapy. This review mainly focuses on the role of metabolic alterations, including glucose, amino acid, lipid, nucleotide and other ion metabolism, in radioresistance, and proposes possible therapeutic targets to improve the efficacy of cancer radiotherapy.

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Section: Amino Acid Metabolism and Cancer Radioresistancementioning

confidence: 99%

“…An appropriate amount of NO can promote tumor growth; however, either too low or too high a level of NO will limit the proliferation of tumor cells. Since arginine is a precursor to NO 112 , 113 , it may explain the contradiction between ADT and oral L-arginine.…”

Section: Amino Acid Metabolism and Cancer Radioresistancementioning

confidence: 99%

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

Yu¹,

Yu²,

Ge³

et al. 2023

Int. J. Biol. Sci.

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“…With accompanying ICD, more mature DC infiltrations (Figure m) and increased secretions of various lymphatic chemokines (Figure s) indicate that the recruitment of effector T cells in tumors will be gradually escalated. In addition, the residual l -Arg is also inferred to contribute to the enhanced immunotherapy due its immune potentiation effects. − These compelling results and multiple immune-stimulant actions adequately validate that such intratumorally synthesized in situ Au bioreactor-enhanced microwavegenetics can propel immune activation, immune cell infiltration, ITM mitigation, and reverse immune-desert TME, which can highlight CAT-T cell infiltrations into solid tumors.…”

Section: Resultsmentioning

confidence: 82%

Extracellular Matrix Viscosity Reprogramming by In Situ Au Bioreactor-Boosted Microwavegenetics Disables Tumor Escape in CAR-T Immunotherapy

et al. 2023

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Incomplete microwave ablation (iMWA) caused by uncontrollable heat diffusion enhances the immunosuppressive tumor microenvironment (ITM), consequently disabling the prevalent immune checkpoint blockade-combined immunotherapy against tumor recurrence. Herein, we successfully constructed an intratumorally synthesized Au bioreactor to disperse heat in thermally sensitive hydrogel-filled tumors and improve the energy utilization efficiency, which magnified the effective ablation zone (EAZ), counteracted iMWA, and simultaneously established and enhanced multiple biological process-regulated microwavegenetics. More significantly, we identified the extracellular matrix (ECM) viscosity as a general immune escape "target". After remodeling ECM, including ECM ingredients and cell adhesion molecules, this physical target was blocked by viscosity reprogramming, furnishing an effective tool to regulate the viscosity target. Thereby, such in situ Au bioreactor-enlarged EAZ and enhanced microwavegenetics reversed the immune-desert tumor microenvironment, mitigated ITM, secreted immune cell-attracting chemokines, recruited and polarized various immune cells, and activated or reactivated them like dendritic cells, natural killing cells, M1-type macrophages, and effector CD8+ or CAR-T cells. Contributed by these multiple actions, the in situ oncolytic Au bioreactors evoked CAR-T immunotherapy to acquire a considerably increased inhibition effect against tumor progression and recurrence after iMWA, thus providing a general method to enhance iMWA and CAR-T immunotherapy.

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“…[38] In this study, we observed a significant metabolic behavior change in melanoma cells after APAP-P-NO treatment, which was probably due to the inactivation of metabolism-related key enzymes upon S-nitrosylation modification. [39] Of note, most immunosuppressive metabolites in the TME, such as lactate, are secreted by tumor cells themselves, and thus ONOO − mediated intracellular metabolic homeostasis disruption may cut off the metabolic crosstalk between tumor cells and the TME, favoring antitumor immune responses. [40] Indeed, this highly specific ONOO − intervention effectively reversed the immunosuppressive TME via TAMs polarization from M2-type to M1-type, reduction of MDSCs and Tregs, and CD8 + T cells restoration, eventually turning immunologically "cold" tumors "hot".…”

Section: Discussionmentioning

confidence: 99%

Tumor‐Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy

et al. 2023

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Tumor cells elicit metabolic reprogramming to establish an immunosuppressive tumor microenvironment (TME) for escaping from immunosurveillance. Therefore, interrupting the metabolic adaptation of tumor cells may be a promising strategy for TME immunomodulation, favoring immunotherapy. In this work, a tumor-specific peroxynitrite nanogenerator APAP-P-NO is constructed that can selectively disrupt metabolic homeostasis in melanoma cells. Stimulated by melanoma-characteristic acid, glutathione, and tyrosinase, APAP-P-NO can efficiently generate peroxynitrite through the in situ coupling of the produced superoxide anion and released nitric oxide. Metabolomics profiling reveals that the accumulated peroxynitrite induces a great decrease in metabolites in the tricarboxylic acid cycle. Meanwhile, the glycolysis-produced lactate drops sharply both intracellularly and extracellularly under peroxynitrite stress. Mechanistically, peroxynitrite impairs the activity of glyceraldehyde-3-phosphate dehydrogenase in glucose metabolism through S-nitrosylation. The metabolic alterations effectively reverse the immunosuppressive TME to evoke potent antitumor immune responses, including polarization of M2-like macrophages to M1phenotype, reduction of myeloid-derived suppressor cells and regulatory T cells, and restoration of CD8 + T cell infiltration. Combining APAP-P-NO with anti-PD-L1 achieves a significant inhibition against both primary and metastatic melanomas without systemic toxicities. Collectively, a tumor-specific peroxynitrite overproduction approach is developed and the possible mechanism of peroxynitrite-mediated TME immunomodulation is explored, providing a new strategy for facilitating immunotherapy sensitivity.

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The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases

Abstract: Arginine enhances the effect of radiation in patients with brain metastasis by metabolic suppression of cancer cells.

Cited by 25 publications

References 60 publications

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy

Extracellular Matrix Viscosity Reprogramming by In Situ Au Bioreactor-Boosted Microwavegenetics Disables Tumor Escape in CAR-T Immunotherapy

Tumor‐Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy

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