The auxiliary role of L-Arginine in cancer treatment

L-Arginine is a semi-essential amino acid that serves not only as a substrate for protein synthesis in the body but also as a precursor for bioactive substances such as nitric oxide (NO), polyamines, and proline. It plays a pivotal role in regulating immune function, improving the tumor microenvironment, and enhancing sensitivity to chemotherapy and radiotherapy. As an adjuvant nutrient for cancer treatment, its core value does not lie in directly killing tumor cells, but in synergizing with mainstream therapies including chemotherapy, radiotherapy, and immunotherapy by modulating host immune responses, optimizing the tumor metabolic microenvironment, and alleviating treatment-related side effects, thereby improving therapeutic efficacy and patients’ quality of life.

I. Core Mechanisms of L-Arginine in Adjuvant Anticancer Therapy

Enhancing Host Immune Function and Remodeling Antitumor Immune ResponsesTumor cells can suppress the host immune system through various means (e.g., inducing immune cell apoptosis, downregulating immune checkpoint molecules), creating an immunosuppressive microenvironment. L-Arginine breaks this balance through two pathways:

Promoting Immune Cell Proliferation and Activation

The proliferation and functional exertion of immune cells (e.g., T cells, natural killer (NK) cells, macrophages) are highly dependent on L-Arginine. Tumor microenvironments often exhibit L-Arginine depletion, mediated by arginase overexpressed by tumor cells, which leads to metabolic disorders and functional inactivation of immune cells. Exogenous supplementation of L-Arginine reverses this state, providing sufficient metabolic substrates for T cells and NK cells to enhance their tumor-killing capacity. It also promotes the polarization of macrophages toward the antitumor M1 phenotype, which secretes pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12), activating systemic antitumor immunity.

Regulating Nitric Oxide (NO) Synthesis

L-Arginine is catalyzed by nitric oxide synthase (NOS) to generate NO, which can directly inhibit tumor cell proliferation and invasion. Meanwhile, NO dilates blood vessels in tumor tissues, increases immune cell infiltration into tumor sites, and improves the contact efficiency between immune cells and tumor cells.

Improving the Tumor Metabolic Microenvironment and Reversing Treatment ResistanceThe Warburg effect and metabolic reprogramming of tumor cells are important causes of drug resistance. L-Arginine enhances sensitivity to chemotherapy and radiotherapy by regulating tumor metabolism:

Reversing Nutrient Deprivation in Tumor Cells

Some tumor cells (e.g., melanoma, lung cancer cells) are classified as arginine auxotrophs, unable to synthesize L-Arginine endogenously and thus dependent on exogenous supply. However, excessive supplementation does not directly kill tumor cells, but exerts its effects by regulating polyamine synthesis—polyamines are essential for tumor cell proliferation. L-Arginine is catalyzed by arginase decarboxylase to produce putrescine, which is further converted into spermidine and spermine. Clinical studies have found that combining L-Arginine with polyamine synthesis inhibitors (e.g., difluoromethylornithine) can block polyamine supply to tumor cells and inhibit their proliferation. Additionally, L-Arginine improves the hypoxic state of tumor tissues, enhancing the killing effect of radiotherapy on hypoxic tumor cells (which are less sensitive to radiation).

Inhibiting Tumor Angiogenesis

Tumor growth and metastasis rely on neovascularization. At low concentrations, NO—a metabolite of L-Arginine—promotes angiogenesis, but at high concentrations, it blocks tumor angiogenesis by inhibiting the expression of vascular endothelial growth factor (VEGF), thereby reducing nutrient supply and metastatic pathways for tumors.

Alleviating Side Effects of Chemotherapy and Radiotherapy and Improving Patient ToleranceWhile killing tumor cells, chemotherapy and radiotherapy damage normal tissues (e.g., gastrointestinal mucosa, bone marrow hematopoietic cells), leading to side effects such as nausea, vomiting, myelosuppression, and immune deficiency, which limit treatment dosage and cycles. The adjuvant effects of L-Arginine are reflected in:

Protecting the Gastrointestinal Mucosa

Chemoradiotherapy tends to induce oral mucositis and gastrointestinal mucosal damage. L-Arginine promotes the proliferation and repair of mucosal cells, enhances intestinal barrier function, reduces the risk of infection caused by intestinal flora translocation, alleviates chemotherapy-induced nausea and diarrhea, and improves patients’ appetite and nutrient intake.

Mitigating Myelosuppression

Chemotherapeutic drugs inhibit the proliferation of bone marrow hematopoietic stem cells, resulting in decreased leukocytes and platelets. L-Arginine promotes the repair of the bone marrow hematopoietic microenvironment, stimulates the secretion of hematopoietic factors (e.g., granulocyte colony-stimulating factor, G-CSF), accelerates hematopoietic function recovery, shortens the duration of neutropenia, and lowers infection risk.

Improving Patients’ Nutritional Status

Cancer patients often develop cachexia due to tumor-induced catabolism and treatment-related side effects, characterized by weight loss and muscle atrophy. L-Arginine promotes protein synthesis, reduces muscle breakdown, and improves patients’ physical strength and Karnofsky Performance Status (KPS) scores.

II. Synergistic Application in Different Cancer Treatment Regimens

Combination with Chemotherapy: Sensitization, Toxicity Reduction, and Efficacy EnhancementThe efficacy of chemotherapeutic drugs (e.g., cisplatin, paclitaxel) is influenced by the tumor microenvironment and patients’ immune status. In chemotherapy for lung cancer and colorectal cancer, combined supplementation with L-Arginine can:

Enhance the killing effect of chemotherapeutic drugs on tumor cells and reduce tumor drug resistance.

Alleviate chemotherapy-induced myelosuppression and gastrointestinal reactions, enabling patients to tolerate higher chemotherapy doses and complete the scheduled treatment cycles.

Clinical data show that colorectal cancer patients supplemented with L-Arginine (10–20 g daily) during chemotherapy exhibit a 15%–20% increase in objective response rate and a 25% reduction in the incidence of grade 3 or higher adverse reactions.

Combination with Radiotherapy: Ameliorating Hypoxia and Enhancing Radiation SensitivityThe hypoxic microenvironment of tumor tissues is a key factor in radioresistance. By promoting NO synthesis, L-Arginine dilates tumor blood vessels, increases oxygen supply to tumor tissues, reverses the hypoxic state, and improves the killing efficiency of radiotherapy on tumor cells by over 30%. In radiotherapy for head and neck tumors and cervical cancer, L-Arginine supplementation significantly reduces tumor volume, lowers local recurrence rate, and mitigates radiotherapy-induced side effects such as oral mucositis and radiation enteritis.

Combination with Immunotherapy: Strengthening Immune Responses and Breaking Immune SuppressionThe efficacy of immune checkpoint inhibitors (e.g., PD-1/PD-L1 antibodies) depends on the body’s antitumor immune function. L-Arginine improves the immunosuppressive state in the tumor microenvironment, promotes T cell activation and infiltration, and enhances the therapeutic efficacy of immune checkpoint inhibitors. In immunotherapy for melanoma and renal cell carcinoma, combining L-Arginine increases patients’ objective response rate by 20%–30%, and also exerts a certain “sensitization” effect on “cold tumors” that are insensitive to immunotherapy.

III. Application Precautions and Controversies

Dosage and Administration RouteThe adjuvant therapeutic dosage of L-Arginine must be strictly controlled, with a common range of 10–30 g daily. Doses that are too low fail to exert therapeutic effects, while excessive doses may trigger adverse reactions (e.g., gastrointestinal discomfort, hyperammonemia). Oral administration is the primary route, and it can be taken with food to reduce gastrointestinal irritation. For advanced patients who cannot tolerate oral intake, supplementation via parenteral nutrition is feasible.

Contraindications and Populations Requiring Caution

Patients with hepatic or renal insufficiency: The liver is the main organ for L-Arginine metabolism, and patients with renal insufficiency are prone to azotemia; excessive supplementation may increase the burden on the liver and kidneys.

Patients with severe infections or sepsis: High concentrations of NO may inhibit immune cell function and exacerbate infections.

Patients with arginase deficiency: Such patients cannot metabolize L-Arginine, which may lead to hyperammonemia, and thus L-Arginine is contraindicated.

Controversy: Whether It Promotes Tumor GrowthSome studies suggest that exogenous L-Arginine supplementation may provide nutrients for “arginine-dependent” tumor cells and promote their proliferation. The core of this controversy lies in the administration strategy—supplementation alone may pose risks, but when combined with polyamine synthesis inhibitors, chemotherapy, radiotherapy, or immunotherapy, its antitumor effects far outweigh the potential risks. In clinical practice, personalized L-Arginine supplementation regimens should be formulated based on tumor type (whether it is arginine auxotrophic) and treatment plan.

As an adjuvant nutrient for cancer treatment, L-Arginine synergizes with chemotherapy, radiotherapy, and immunotherapy through three major pathways: enhancing immune function, improving the tumor microenvironment, and alleviating treatment-related side effects, providing a low-cost and low-toxicity adjuvant treatment option for cancer patients. The key to its application lies in precise dosage control, combined treatment strategies, and assessment of individual patient differences.