Abstract
The immune system plays an essential role in protecting the host from malignant transformation through immune surveillance, a concept that was later expanded by the cancer immunoediting framework. While immune responses eliminate emerging tumors, they can also impose selective pressure that promotes tumor adaptation and immune escape. Among the mechanisms involved in this process, metabolic immune suppression has gained increasing attention, as it weakens immune function without causing immune cell death. In this context, the semi-essential amino acid L-arginine has emerged as an important metabolic factor regulating immune competence within the tumor microenvironment. The availability of arginine directly affects immune cell activation, proliferation, and effector function, acting as a metabolic checkpoint rather than only as a biosynthetic substrate. Tumors actively generate arginine-poor niches through the expression of arginine- metabolizing enzymes in tumor cells as well as in immunosuppressive myeloid and stromal populations. As a result, immune cells, particularly T lymphocytes, undergo a reversible state of functional paralysis characterized by preserved viability but impaired cell-cycle progression, reduced protein synthesis, and weakened effector responses. In contrast, tumor cells often tolerate or adapt to low arginine levels, leading to a metabolic imbalance that selectively suppresses antitumor immunity. In this review, we summarize current knowledge on arginine- dependent immune suppression, focusing on arginase- and nitric oxide synthase–mediated pathways, competition for arginine transport, and nutrient-sensing signaling through mTORC1 and GCN2. We also discuss the evolutionary conservation and reversibility of this mechanism and its interplay with other immunosuppressive metabolic pathways. Finally, we highlight therapeutic strategies targeting arginine metabolism, emphasizing the arginine system as a key regulator of tumor-induced immune suppression and a potential target for cancer immunotherapy.
Introduction
It has long been recognized that the immune system, in addition to its role in protecting the host against invading pathogens, is critically involved in the recognition and elimination of aberrant cells arising within the organism itself, including tumor cells expressing abnormal antigens. This concept, historically framed as immune surveillance, is supported by extensive experimental and clinical evidence demonstrating that immune competence is essential for the prevention of malignant transformation and tumor progression. The subsequent formalization of these observations into the framework of cancer immunoediting further refined this view, proposing that immune system not only is able to eliminate emerging tumors but also shapes tumor evolution through sequential phases of elimination, equilibrium, and escape (1). From a clinical perspective, the relevance of immune surveillance is underscored by the increased cancer risk observed in immunosuppressed states. Multiple studies have documented elevated incidences of several malignancies in patients receiving long-term immunosuppressive therapy after organ transplantation, as well as in individuals with chronic immune dysfunction such as HIV/AIDS (2). Taken together, these data support the idea of immune surveillance as a basic and evolutionarily conserved physiological function. The idea that immune activation can counteract tumor growth has been postulated before the modern immunology. More than a century ago, William B. Coley reported that the induction of strong inflammatory responses through bacterial inoculations could, in a subset of cases, lead to tumor regression. Although the underlying mechanisms were unclear at the time, these observations provided early evidence that immune responses could be therapeutically harnessed against cancer (3). Subsequent work has shown that such immune pressure exerts sustained specific and selective forces on tumor cells, driving the emergence of different immune escape strategies that are now recognized as central to the immunoediting process (1). Therefore, the current view assigns to the immune system a dual role in cancer: i) tumor foe, by destroying cancer cells or inhibiting their outgrowth but also ii) tumor supporter, by selecting cancer cells able to survive in immunocompetent host or by shaping favorable tumor microenvironment (4). Immunotherapy, whose aim is to induce an immune-mediated anti-tumor response, may exert a similar immune pressure prompting treated tumors to start another round of immunoediting (5).
The functional paralysis as a strategy to sustain a metabolic immune-escape. Among escape mechanisms, growing attention has been directed toward those that exploit the metabolic vulnerabilities of immune cells. Rather than killing immune cells directly, tumors frequently remodel the metabolic landscape of the tumor microenvironment in ways that specifically impair immune activation, proliferation, and effector function. This form of metabolic suppression is particularly effective, as it disables antitumor immunity while preserving immune cell viability. A consistent feature of this process is that immune cells in such environments rarely undergo cell death; instead, they enter a state of “functional paralysis”, characterized by cell-cycle arrest, attenuated activation, and reduced cytokine production, while remaining metabolically and structurally intact (6, 7). The functional paralysis may involve both innate and adaptive immune cells (8), by exploiting nutrient deficiencies related to the tumor microenvironment (9) or feedback mechanisms related to chronic immune stimulation (10). Mutant selection may lead to the unbalancing of specific metabolite(s) in tumor cells, which in turn freezes the immune response (11). Within this context, the semi-essential amino acid L-arginine has emerged as a central metabolic node linking tumor-driven microenvironmental reprogramming to immune dysfunction. Beyond serving as a biosynthetic building block for proteins and metabolites (12), arginine functions as an extracellular signal and its availability directly influences immune cell responsiveness. Arginine levels are controlled by its supplementation (including dietary income and de novo biosynthesis from glutamate, glutamine and proline) and catabolism, including the arginase activity and the nitric oxide synthesis (NOS) activities. Mammals express two arginase isoforms (Arg1 and Arg2), differently distributed, with Arg1 transcriptionally controlled by cytokines in selected tissues (beyond its constitutive hepatic role in the urea cycle) and Arg2 showing a more ubiquitous and constitutive expression pattern. NOS catabolizes arginine yielding nitric oxide (NO) and citrulline; among the three isoforms found in mammals, NOS2 is the prevalent isoform in immune cells, where it is not constitutively expressed, but is strongly induced by lipopolysaccharide (LPS) and inflammatory cytokines [also named inducible NOS (iNOS)]. Therefore, arginine catabolism is strictly linked to both immune modulation and signaling cascades; a crosstalk between the two systems takes place to counterbalance the strong inflammatory effect of NO burst (12). A summary of the metabolic and regulatory pathways controlling arginine steady state is reported in Figure 1. Seminal studies demonstrated that reduction of extracellular arginine per se is sufficient to profoundly impair T-cell function without affecting cell survival, thereby uncoupling immune cell presence from immune competence (6, 13). Importantly, tumor cells and immune cells coexist within the same arginine-depleted niche yet respond very differently to this constraint. Whereas immune cells exhibit acute functional impairment, tumor cells frequently tolerate or adapt to low-arginine conditions. This metabolic asymmetry generates selective pressure that favors immune suppression (14, 15). Collectively, these findings support the view that arginine depletion is not merely a passive consequence of tumor growth but represents an actively imposed microenvironmental condition that exploits differential metabolic tolerance to enforce immune paralysis.
Schematic overview of metabolic pathways involved in arginine steady-state. Arg: Arginase; NOS: nitric oxide synthase; ASS-1 argininosuccinate synthase 1. Arginase and NOS activity compete for arginine; NOS1: the neuronal form involved in neurotransmission and synaptic plasticity; NOS2: the inducible form involved in the immune response; NOS3: the endothelial form, mainly responsible for vasodilation.
Arginine-dependent Signaling at the Tumor–immune Interface
Evolutionary conservation of arginine-dependent immunosuppression. Arginine-dependent immunosuppression is not unique to cancer but reflects an evolutionarily conserved strategy of immune regulation. Several intracellular pathogens, including Mycobacterium spp., Helicobacter pylori, and Leishmania major, similarly manipulate host arginine metabolism by inducing arginase expression in myeloid cells. This results in reduced extracellular arginine availability and the establishment of immunosuppressive microenvironment that facilitate immune evasion (13, 16). The convergence of strategies employed by pathogens and tumors highlights arginine depletion as a broadly utilized mechanism for attenuating immune competence while preserving immune cell survival.
Arginine limitation as a reversible checkpoint in T cells. In immune cells, particularly T lymphocytes, arginine availability primarily regulates functional competence rather than viability. Arginine deprivation suppresses proliferation, limits protein translation, and reduces effector molecule expression, thereby inducing a reversible state of functional paralysis without triggering cell death (6, 7). At the intracellular level, T cells exposed to arginine depletion retain proximal T-cell receptor signaling and early activation markers but fail to progress through the G1–S cell-cycle checkpoint. This arrest is associated with defective induction of cyclin D3 and CDK4, reduced phosphorylation of retinoblastoma protein, and impaired E2F-dependent transcriptional programs (13). The rapid restoration of immune function following arginine repletion indicates that this state reflects functional anergy rather than irreversible cellular damage. Importantly, this reversibility has significant therapeutic implications, as it suggests that immune dysfunction imposed by arginine deprivation is not fixed but can, in principle, be pharmacologically or metabolically corrected (Figure 2, supplementation path). Mechanistically, conserved nutrient-sensing pathways, most notably the kinase GCN2, link extracellular arginine scarcity to translational control and proliferative arrest (17).
Scheme of the effect on T-cell of tumor-driven arginine depletion.
Tumor-driven arginine depletion by myeloid and stromal populations. In specific tumor subsets, notably those prone to brain metastasis, tumor cells have been reported to directly upregulate arginine-metabolizing enzymes such as arginase 2 (ARG2), implicating cell-intrinsic arginine metabolism in tumor adaptation to the metastatic niche (18) (Figure 2). In other cases specific tumor types, through the secretion of factors such as G-CSF, GM-CSF, and CCL2, promote the recruitment and polarization of immunosuppressive myeloid populations, including myeloid-derived suppressor cells (MDSCs) and M2-like macrophages (19). These cells exhibit high arginase expression and activity, functioning as metabolic sinks that deplete local arginine pools (20) (Figure 2). Notably, arginine-depleting capacity is not restricted to immune cells; stromal components such as cancer-associated fibroblasts can also express ARG2, thereby adding an additional layer of non–cell-autonomous control over the metabolic state of the tumor microenvironment (21, 22) (Figure 2).
Competition for arginine transport and nutrient-sensing via mTORC1. This immunosuppressive landscape is shaped by intense metabolic competition for a limiting resource. Tumor cells frequently overexpress arginine transporters, including SLC6A14, SLC7A3, and SLC7A9, to sustain elevated anabolic demands (23, 24) (Figure 2). Activated T cells similarly upregulate amino acid transporters to support the metabolic reprogramming required for effector responses (25, 26). Once internalized, arginine also acts as a potent metabolic signal, activating mTORC1 through a network of spatially distinct sensors, including cytosolic CASTOR1, the lysosomal SLC38A9–v-ATPase complex, and modulation of the TSC complex (27-29). This redundancy helps explain why arginine is a particularly potent activator of mTOR and why its withdrawal rapidly suppresses anabolic programs.
Downstream arginine utilization and nitric oxide complexity. These observations raise a broader question regarding arginine utilization downstream of uptake. In principle, elevated arginine flux could be partitioned between sustaining mTOR-driven anabolic metabolism and supporting NO synthesis, for which arginine is the obligate substrate. NO is a pleiotropic signaling molecule with context-dependent roles in cancer, having been linked to angiogenesis, metastasis, resistance to apoptosis, and immune suppression, as well as to modulation of oncogenic signaling pathways such as mTOR through S-nitrosylation (30, 31). Additional complexity arises from the fact that NO within the tumor microenvironment is not exclusively tumor-derived; myeloid cells can produce high levels of NO via iNOS, which in certain contexts directly contributes to T-cell dysfunction through mechanisms distinct from arginine deprivation (32). At present, however, dynamic regulation of arginine flux partitioning within tumor cells remains speculative and awaits direct experimental validation.
Arginine deprivation as a coordinated metabolic stress program and integrated immunosuppressive metabolism. Arginine deprivation also induces a coordinated metabolic stress response characterized by inhibition of mTOR and PI3K/Akt signaling, activation of AMPK, induction of autophagy, and engagement of the integrated stress response mediated by GCN2 and ATF4 (28, 33). Many tumors lack a normal capacity to replenish intracellular arginine when extracellular arginine becomes limiting, because they have deficient ASS1 activity and therefore cannot efficiently resynthesize arginine from citrulline. In ASS1-deficient tumors, mTOR inhibition due to arginine deprivation culminates in mitochondrial dysfunction and depletion of critical metabolites such as aspartate, whereas immune cells remain highly sensitive even to modest reductions in arginine availability. This metabolic asymmetry enables tumors to exploit arginine depletion as a reversible immune escape strategy. Importantly, arginine-dependent suppression rarely operates in isolation but instead cooperates with other immunosuppressive metabolic pathways, including tryptophan catabolism via the IDO/TDO–kynurenine axis, adenosine accumulation mediated by CD39/CD73, and lactate-driven acidification, collectively shaping an integrated immunosuppressive metabolic environment (34, 35).
Translational and Therapeutic Perspectives
As mentioned above, the arginine system emerges as a key regulator of tumor-induced immune suppression, thereby positioning it as a potential target for cancer immunotherapy in distinct biological and clinical settings.
Arginase inhibition to restore extracellular arginine. Mechanistic insights into arginine-dependent immune suppression are increasingly informing therapeutic strategies aimed at modifying the metabolic constraints of the tumor microenvironment. One direct approach involves pharmacological inhibition of arginase to restore extracellular arginine availability and alleviate myeloid-mediated immune suppression. In preclinical studies, the arginase inhibitor CB-1158 (INCB001158) restored T- cell proliferation, enhanced antitumor immunity, and synergized with immune checkpoint blockade (36). Early- phase clinical trials with INCB001158 have demonstrated pharmacodynamic target engagement and acceptable tolerability, although its efficacy as a single agent in unselected patient populations appears limited, supporting its evaluation in rational combination strategies (37).
Arginine deprivation therapies in ASS1-deficient tumors and biomarker considerations. A conceptually distinct therapeutic strategy exploits the arginine auxotrophy of ASS1-deficient tumors. In this setting, enzymatic depletion of systemic arginine, for example through pegylated arginine deiminase, functions as a tumor-directed metabolic therapy. This approach, however, raises important considerations regarding the balance between tumor cytotoxicity and preservation of immune cell function (38). Both strategies underscore the need for careful patient stratification. ASS1 expression represents a validated biomarker for deprivation-based therapies, whereas circulating arginine levels and arginase activity may help guide arginase inhibition strategies. The predictive value of these biomarkers for clinical outcomes, however, remains to be established prospectively.
Conclusion
The evidence discussed here supports a shift in perspective in which extracellular arginine is viewed not merely as a metabolic substrate but as a key environmental signal governing immune competence within the tumor microenvironment. Its availability functions as a metabolic checkpoint that determines whether immune cells can transition from activation to effective proliferation and antitumor effector function. Tumors exploit this dependency by actively establishing arginine-depleted niches. Rather than eliminating immune cells, this strategy induces a reversible state of functional paralysis that preserves immune cell viability while impairing effector responses, thereby explaining the coexistence of immune infiltration with ineffective immune control. A defining feature of arginine-driven immune suppression is its non–cell-autonomous nature and the resulting metabolic asymmetry between tumor and immune cells. While immune cells are acutely sensitive to arginine limitation, tumor cells frequently tolerate or adapt to this constraint, enabling selective immune suppression. The reversibility of this dysfunction further distinguishes arginine depletion as a regulatory mechanism rather than a degenerative one. By reframing arginine depletion as an active process that exploits fundamental principles of immunometabolism, this framework provides a unifying perspective on how tumors uncouple immune presence from immune function. Recognizing arginine availability as a decisive signal in the tumor–immune dialogue offers a conceptual foundation for integrating metabolic regulation into models of immune escape and for guiding the development of therapeutic strategies targeting the metabolic core of cancer immunosuppression.
Footnotes
Authors’ Contributions
GEB collected and curated the relevant literature. FC, SR, and AP wrote the manuscript. SR and AP critically revised the manuscript, refined the writing, and prepared the figures. All Authors reviewed and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
National Recovery and Resilience Plan (NRRP), Mission 4, Component 2, Investment 1.1, Call No. 104 (2.2.2022) by the Italian Ministry of University and Research (MUR), funded by the European Union – NextGenerationEU – PRIN Project N. CUP N. B53D23015930006 (to F.C.), Project N. CUP N. B53D23016330006 (to S.R.). AIRC (IG 32139); PRIN 2022 (grant number 20228395 KW) and Grant from La Sapienza University RG123188B0602C40 and RM11916B46D48441 to F.C. and RM124191085800CD to A.P. and AR125199C381E0D3 to G.E.B.
Artificial Intelligence (AI) Disclosure
Artificial intelligence tools were used to improve the fluency, clarity, and overall readability of the manuscript. All scientific content, interpretations, and references were carefully verified by the corresponding author. The different cellular components depicted in Figure 2 were generated using AI-based illustration tools.
- Received February 8, 2026.
- Revision received February 19, 2026.
- Accepted February 24, 2026.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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