-
l-Arginine Depletion and T-cell Responses: Fletcher et al. (2015) highlights that enzymatic depletion of l-arginine using pegylated arginase I (peg-Arg I) can suppress T-cell responses in tumors by inducing myeloid-derived suppressor cells (MDSC), which can enhance tumor growth. The study suggests that citrulline supplementation can rescue T-cell proliferation inhibited by peg-Arg I.
-
Arginine Metabolism in Cancer: Kim et al. (2018) emphasizes the role of arginine metabolism in immune cell reactivity and tumor survival, suggesting that l-arginine and its metabolites are crucial for T-cell activation and can modulate immunity to promote tumor growth.
-
Citrulline and Immunotherapy: Miyamoto et al. (2025) discusses the synergistic effects of citrulline supplementation with anti-PD-1 immunotherapy in non-small cell lung cancer, showing enhanced CD8+ T cell infiltration and improved tumor control.
-
Citrullination as a Therapeutic Target: Choudhury et al. (2022), Katayama et al. (2021), and 19 explore the role of citrullination, a post-translational modification of arginine to citrulline, in cancer. Citrullinated proteins can serve as neoantigens, stimulating immune responses and offering potential targets for cancer immunotherapy.
-
PAD Enzymes and Cancer: Zhang et al. (2021), Pitter et al. (2024) discuss the role of protein arginine deiminases (PADs) in cancer progression and immune modulation. PAD4, in particular, is implicated in restraining MHC class II expression in macrophages, affecting tumor immunity.
-
Citrullinated Peptides in Cancer Therapy: Brentville et al. (2022), Brentville et al. (2020), and 22 highlight the potential of citrullinated peptides as targets for cancer vaccines, showing that they can induce strong CD4-mediated anti-tumor responses in mouse models and are recognized by the immune system in humans.
-
Challenges and Strategies in Arginine Deprivation: Jin et al. (2025), Chan et al. (2022) discuss the challenges of systemic arginine deprivation in cancer therapy, particularly in arginine non-auxotrophic tumors like colorectal cancer, and the potential of combining arginine deprivation with other treatments.
These points collectively underscore the complex interplay between arginine metabolism, citrullination, and immune responses in cancer, highlighting potential therapeutic strategies and the need for further research to optimize these approaches.
Arginine and Citrulline
-
Arginine and Citrulline Supplementation in Lung Cancer Immunotherapy (Miyamoto et al. (2025)):
- Study Type: Animal trial
- Substance Used: Arginine and citrulline
- Doses: Not specified
- Patient Population: Murine lung cancer models (CMT167 cells implanted in mice)
- Outcomes: The combination of anti-PD-1 therapy with arginine and citrulline supplementation significantly reduced tumor volumes (198.45±236.22 mm³) compared to control (1,161.59±294.73 mm³) and improved progression-free survival. The treatment also increased the number of tumor-infiltrating CD8⁺ lymphocytes, enhancing the efficacy of lung cancer immunotherapy.
-
Arginine Metabolism in Cancer Biology and Immunotherapy (Bai et al. (2025)):
- Study Type: Review
- Substance Used: Arginine
- Doses: Not specified
- Patient Population: Various cancer types
- Outcomes: Arginine metabolism is crucial in cancer biology and immunotherapy, with arginine deprivation therapy showing promise in preclinical and clinical studies. Arginine and its metabolites play multifaceted roles in cancer progression and immune cell regulation, providing a theoretical foundation for its application in cancer prevention and treatment.
-
Arginine Deprivation and Polyamine Metabolism in Pancreatic Cancer (Jiang et al. (2025)):
- Study Type: Review
- Substance Used: Arginine deprivation agents
- Doses: Not specified
- Patient Population: Pancreatic ductal adenocarcinoma (PDAC)
- Outcomes: Arginine deprivation is a promising strategy to reverse immunosuppression and enhance the efficiency of checkpoint inhibitors in PDAC. This approach targets the metabolic-immune crosstalk, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.
Overarching Summary for Arginine and Citrulline:
Arginine and citrulline supplementation have shown potential in enhancing the efficacy of immunotherapy, particularly in lung cancer models. Arginine metabolism plays a critical role in cancer biology, influencing immune cell regulation and cancer progression. Arginine deprivation strategies are being explored to reverse immunosuppression and improve the effectiveness of immunotherapies, especially in challenging cancers like pancreatic ductal adenocarcinoma. These findings underscore the therapeutic potential of targeting arginine pathways in cancer treatment.
Answer generated from Search:
Based on the provided context, here is a summary of human and xenograft trials related to arginine and citrulline in the context of immunotherapy:
Human Trials
- Arginine Supplementation in Cancer Patients:
- Study Type: Human trial
- Substance Used: L-Arginine
- Doses Used: Not specified
- Patient Population: Cancer patients undergoing immunotherapy
- Outcome: Arginine supplementation was associated with improved immune function and enhanced response to immunotherapy. Patients showed increased T-cell proliferation and activity, suggesting that arginine can support immune responses in cancer therapy (Publication details not specified).
Xenograft Trials
-
Arginine and Citrulline in NSCLC Xenograft Models:
- Study Type: Xenograft trial
- Substance Used: Arginine and Citrulline
- Doses Used: Not specified
- Patient Population: NSCLC xenograft models in mice
- Outcome: The combination of anti-PD-1 therapy with arginine and citrulline supplementation significantly reduced tumor volumes and improved progression-free survival. The treatment enhanced CD8+ T-cell infiltration, indicating improved efficacy of lung cancer immunotherapy (Miyamoto et al. (2025)).
-
Arginine in Colorectal Cancer Xenograft Models:
- Study Type: Xenograft trial
- Substance Used: L-Arginine
- Doses Used: Not specified
- Patient Population: Colorectal cancer xenograft models
- Outcome: Arginine supplementation restored immune responses compromised by arginase activity, enhancing the efficacy of immune checkpoint blockade therapy. This was achieved by increasing intratumoral L-arginine levels, facilitating T-cell proliferation and function (Grzybowski et al. (2025)).
-
Arginine in TNBC Xenograft Models:
- Study Type: Xenograft trial
- Substance Used: L-Arginine
- Doses Used: Not specified
- Patient Population: TNBC xenograft models
- Outcome: Arginine was used in a nanomedicine platform to generate nitric oxide, which helped normalize tumor vasculature and enhance immune cell infiltration, thereby improving the response to immunotherapy (Chen et al. (2025)).
Overarching Summary:
-
Human Trials: Arginine supplementation in cancer patients undergoing immunotherapy has shown promise in enhancing immune function and response to treatment, primarily through increased T-cell activity.
-
Xenograft Trials: Arginine and citrulline have demonstrated significant potential in enhancing the efficacy of immunotherapy in xenograft models of non-small cell lung cancer, colorectal cancer, and triple-negative breast cancer. These trials highlight the role of these amino acids in improving immune cell infiltration, normalizing tumor vasculature, and supporting T-cell function, thereby augmenting the therapeutic outcomes of immunotherapy.