Immunotherapy introduced a deeper concept: the immune system already has the ability to recognize and eliminate abnormal cells, but tumors often learn how to hide, exhaust immune cells, or create an inflammatory and metabolically hostile microenvironment. Therefore, when we talk about supporting immunotherapy, we are not simply referring to “boosting the immune system,” but rather to improving the environment in which immune cells must function.

In this context, several nutritional supplements have attracted interest because they act on fundamental processes involved in the immune response. While they should not be considered anticancer treatments on their own or substitutes for medical therapies, their potential role is to support the body, modulate biological pathways, and possibly help immune cells maintain their function within the demanding tumor microenvironment.

 

Creatine Monohydrate

One of the most interesting examples is creatine monohydrate. Although it is commonly associated with muscle mass and physical performance, creatine also plays an important role in cellular bioenergetics. Cytotoxic T cells require large amounts of energy to recognize tumor antigens, proliferate, produce cytokines, and destroy malignant cells. Preclinical studies have shown that creatine uptake can strengthen T cell-mediated antitumor immunity and improve responses to immune checkpoint blockade therapies such as PD-1 inhibitors.

This is particularly relevant because many tumors create a nutrient-poor, acidic, hypoxic microenvironment filled with inhibitory signals. Under these conditions, T lymphocytes enter a state of functional exhaustion: they recognize the tumor but gradually lose their ability to fight it. Creatine supplementation has therefore been proposed as a strategy to support both muscular and potentially immune energy reserves. In addition, preserving muscle mass during cancer treatment is clinically important, as sarcopenia is associated with poorer treatment tolerance, increased systemic inflammation, and reduced capacity to sustain prolonged therapies.

 

Camu Camu

Camu camu, an Amazonian fruit rich in vitamin C and polyphenols, enters this discussion from a different perspective: antioxidant and inflammatory balance. Vitamin C contributes to both innate and adaptive immune function, supports the activity of phagocytic cells, helps maintain tissue integrity, and serves as a cofactor for enzymes involved in gene regulation. However, in cancer, antioxidant therapy must be approached carefully. The goal is not to eliminate oxidative stress entirely, since some anticancer therapies partially depend on reactive oxygen species to induce tumor damage. Instead, the objective is to modulate excessive inflammation and protect healthy tissues without interfering with therapeutic mechanisms.

Camu camu may offer a more complex biological matrix than isolated vitamin C because it combines ascorbic acid with phenolic compounds. These components may influence markers of inflammation and oxidative stress. Within the context of immunotherapy, its potential value lies in supporting a more stable redox environment, particularly in patients experiencing chronic inflammation, fatigue, or nutritional decline. Nevertheless, direct clinical evidence in cancer immunotherapy remains limited, so it should be presented as nutritional support rather than as a proven enhancer of clinical response.

 

Cetirizine

Cetirizine, commercially known as Zyrtec, may initially seem like an unusual addition because it is an antihistamine primarily used to treat allergies. However, its inclusion becomes more understandable when considering the role of histamine in immune regulation. Histamine can modulate inflammatory and immune responses, and in some patients, cetirizine may help control allergic symptoms, pruritus, or inflammatory reactions associated with treatment, thereby improving treatment tolerance and overall quality of life.

 

Nicotinamide

Nicotinamide, a form of vitamin B3, is connected to one of the most extensively studied metabolic pathways in cancer and immunity: NAD+ metabolism. NAD+ is essential for oxidation-reduction reactions, DNA repair, and cellular energy metabolism. Tumor-infiltrating immune cells often experience metabolic exhaustion, and experimental studies have shown that restoring NAD+-related pathways may improve T-cell function. Consequently, nicotinamide has been proposed as a metabolic modulator of interest.

However, NAD+ metabolism in cancer is highly complex. Increasing NAD+ availability may enhance immune cell function, but it may also benefit certain tumor cells depending on the cancer type, biological context, and treatment strategy. This duality is crucial: the same molecule may support repair and metabolism in healthy or immune cells while simultaneously contributing to tumor survival under specific conditions. Therefore, nicotinamide should be viewed as a metabolic intervention requiring clinical judgment rather than as a universal recommendation.

 

N-Acetyl-L-Cysteine (NAC)

N-acetyl-L-cysteine (NAC) is a precursor of glutathione, one of the body’s most important intracellular antioxidants. Its biological rationale is straightforward: when immune cells are exposed to excessive oxidative stress, they may lose functionality. By supporting glutathione synthesis, NAC may help maintain redox balance, protect mitochondria, and reduce uncontrolled inflammation. In immunotherapy, where immune activation must be both powerful and tightly regulated, maintaining this balance is particularly important.

However, NAC also requires caution. Some preclinical studies have suggested that certain antioxidants may promote tumor progression or metastasis in specific contexts by protecting cancer cells from oxidative stress. This does not mean that NAC is harmful in all cancer patients, but rather that its use should be individualized according to the clinical situation.

 

PQQ

PQQ, or pyrroloquinoline quinone, is less well known but particularly interesting because of its relationship with mitochondrial biology. Mitochondria are not merely energy-producing organelles; they also regulate inflammation, cell death, antiviral signaling, and immune responses. Exhausted T cells often exhibit mitochondrial dysfunction, reduced oxidative capacity, and diminished persistence. PQQ has been investigated for its ability to influence mitochondrial biogenesis, oxidative stress, and inflammation. In this regard, it may help improve the metabolic fitness of cells subjected to chronic stress.

Rather than directly attacking tumors or independently activating antitumor immunity, PQQ may help preserve cellular function in both tissues and immune cells. Nevertheless, clinical evidence specifically involving patients treated with immune checkpoint inhibitors remains insufficient.

 

Alpha-Ketoglutarate (AKG)

Alpha-ketoglutarate (AKG) functions as a metabolic signal that informs the cell about its energetic and functional status. This is particularly important in immunotherapy because antitumor T cells must sustain an effective program characterized by continuous cytotoxic activity while resisting exhaustion. If cellular metabolism fails to support these demands, immune responses gradually decline. AKG supplementation has therefore been proposed as a potential metabolic strategy to support immune function and enhance immunotherapy.

 

Figure 1. These compounds contribute to energy production, mitochondrial function, redox balance, and methylation, helping maintain immune cell fitness and resilience within the tumor microenvironment. 

 

Glycine

Glycine is a simple amino acid with remarkable biological versatility. It has demonstrated anti-inflammatory properties in several experimental models. In cancer patients, where systemic inflammation, oxidative stress, muscle wasting, and tissue injury frequently coexist, glycine may serve as a metabolic building block that supports tissue repair and physiological balance. Its potential role includes promoting antioxidant synthesis and facilitating tissue recovery.

However, glycine should also be interpreted cautiously. Amino acids can be utilized by both immune cells and tumor cells. The critical question is not whether a molecule is inherently “good” or “bad,” but rather under which metabolic circumstances it is administered. In immunotherapy, the goal is to ensure that immune cells have adequate metabolic resources without simultaneously fueling pathways that tumors may exploit. Consequently, glycine is best viewed as part of a supervised nutritional strategy rather than as an isolated intervention.

 

TMG

TMG, also known as trimethylglycine or betaine, functions as a methyl-group donor and osmoprotectant. Its involvement in one-carbon metabolism links it to methylation processes. Methylation influences gene expression, cellular repair, and inflammatory regulation. In addition, betaine has been investigated for its anti-inflammatory properties, making these pathways potentially relevant in patients undergoing cancer treatment as they strive to maintain systemic homeostasis.

TMG may contribute to overall metabolic support, particularly when the goal is to preserve liver function, methylation capacity, and stress responses. However, as with nicotinamide and AKG, discussing methylation in cancer requires caution. Epigenetic pathways may support tissue repair and immune function, but they can also contribute to tumor plasticity. Therefore, individualized clinical evaluation remains essential.

When these nine compounds are considered together, a coherent picture emerges: they are not “anticancer supplements,” but rather modulators of the biological environment. Creatine and AKG primarily support energy metabolism. Nicotinamide and PQQ are associated with mitochondrial function and NAD+ metabolism. NAC, camu camu, and glycine contribute to redox balance. TMG supports methylation and stress responses. Cetirizine contributes to inflammatory control and treatment tolerability. Together, they converge on one central concept: for immunotherapy to be effective, the immune system must be able to recognize tumors, infiltrate them, sustain adequate energy, resist exhaustion, regulate inflammation, and maintain functional precision.

Immunotherapy does not occur in isolation. It takes place within a living organism that includes muscle, the microbiota, the liver, mitochondria, oxidative stress, sleep, nutrition, inflammation, and medications. For this reason, the future of cancer treatment will likely involve not only selecting the appropriate therapeutic antibody but also complementing it with intelligent metabolic and nutritional strategies. Even so, science is still determining which combinations are beneficial, which patients are most likely to benefit, and the optimal timing for these interventions during cancer treatment.

 

Main reference:

Leone, R. D., & Powell, J. D. (2020). Metabolism of immune cells in cancer. Nature reviews. Cancer, 20(9), 516–531. https://doi.org/10.1038/s41568-020-0273-y 

 

Other references:

Di Biase, S., Ma, X., Wang, X., Yu, J., Wang, Y. C., Smith, D. J., Zhou, Y., Li, Z., Kim, Y. J., Clarke, N., To, A., & Yang, L. (2019). Creatine uptake regulates CD8 T cell antitumor immunity. The Journal of experimental medicine, 216(12), 2869–2882. https://doi.org/10.1084/jem.20182044 

Jutel, M., Akdis, M., & Akdis, C. A. (2009). Histamine, histamine receptors and their role in immune pathology. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 39(12), 1786–1800. https://doi.org/10.1111/j.1365-2222.2009.03374.x