A recent study in Nature Communications revealed how vitamin C enhances immunotherapy for liver cancer. Vitamin C activates the TET2 gene, which increases cGAS expression, leading to the production of cGAMP. This molecule is transported via the LRRC8C channel into vascular endothelial cells, activating the STING pathway. This cascade normalizes tumor blood vessels, boosts CD8+ T cell infiltration, and alleviates immunosuppression. In mouse models, combining high-dose vitamin C with anti-PD-L1 therapy significantly improved anti-tumor efficacy compared to monotherapy. While promising as a therapeutic adjuvant, adherence to recommended vitamin C intake (100mg/day for adults, upper limit 2000mg/day) is advised. This research offers a novel strategy to improve liver cancer immunotherapy.
Imagine walking into a grocery store and passing by the supplement aisle—rows of colorful bottles catch your eye, and among them, vitamin C supplements stand out as one of the most popular choices. From preventing colds to boosting immunity, this humble vitamin has long been a household name. But what if we told you that beyond its common health benefits, vitamin C is now making waves in the fight against one of the deadliest diseases—cancer? Recent groundbreaking research has uncovered a remarkable role of vitamin C in enhancing cancer immunotherapy, opening up new hope for patients.
As we all know, vitamins are one of the six major nutrients required by the human body, and they are also essential micronutrient organic compounds for maintaining normal human life and health. For most vitamins, the human body cannot synthesize them directly or the amount synthesized is very small, which is insufficient to meet the needs of the body. Therefore, they must be supplied by food to maintain normal life activities and physiological functions.
With the popularization of nutritional concepts, people are paying more and more attention to the role of vitamins. They are even not satisfied with obtaining vitamins only from natural foods and have begun to take them actively, such as taking some "vitamin supplements", especially the highly popular vitamin C.
The public is no stranger to vitamin C. Vitamin C is also known as "ascorbic acid". From 1747 when a British naval surgeon found a way to help humans overcome scurvy, to 1933 when vitamin C was first artificially synthesized and became the first vitamin supplement to enter the market, human exploration of vitamin C has never stopped.
A large number of studies have shown that vitamin C is of great significance to health. In the human body, vitamin C has important physiological functions and is widely involved in metabolic processes such as oxidation, reduction, and hydroxylation in the human body. In addition, it participates in the synthesis of various hormones, neurotransmitters, and proteins.
Previously, a research team from China revealed another important role of vitamin C—administering vitamin C can activate the tumor suppressor gene TET2, induce the normalization of tumor blood vessels, and thus improve the efficacy of immunotherapy with anti-PD-L1 alone or in combination with IL-2. This study was published in Nature Communications.
DOI: 10.1038/s41467-023-43743-9
With the development of medicine and the deepening of scientific research, more and more cancer treatment methods have emerged and been applied in clinical practice, bringing new treatment approaches and hopes to cancer patients. People have gradually changed from "talking about cancer with fear" to "coexisting with cancer". At present, immune checkpoint blocking therapy, especially antibodies targeting the programmed cell death (PD-1)/programmed cell death ligand (PD-L1) pathway, has achieved remarkable results in the treatment of various malignant tumors.
However, the reality is that anti-PD-1/PD-L1 monotherapy can only continue to work in some cancer patients, while some will relapse after a period of treatment. In fact, the key factor hindering the efficacy of immunotherapy is the abnormal tumor blood vessels and the resulting series of hypoxia and immunosuppressive tumor microenvironment, especially in liver cancer with strong angiogenesis.
Based on this, if we can effectively "anti-angiogenesis", many problems can be solved—not only can the abnormal tumor blood vessels return to normal, improving the infiltration of immune effector cells in the tumor; it can also reverse the immunosuppressive microenvironment induced by angiogenesis inducers (such as vascular endothelial growth factor VEGF).
The Role of cGAS-STING Pathway in Anti-Tumor Immunity
In this regard, researchers have explored a very important anti-tumor immune response pathway existing in immune cells—the cGAS-STING pathway.
Cyclic GMP-AMP synthase (cGAS) is a cell membrane DNA sensor that can produce the second messenger cyclic (cGAMP), bind to and activate the stimulator of interferon genes (STING), thereby triggering the innate immune response. Furthermore, the activated cGAS-STING pathway plays an important role in anti-tumor immunity through T cell priming.
First, in the established mouse model, the researchers observed an important phenomenon: the higher the expression of Cgas in cancer cells, the smaller the tumor burden in mice, and at the same time, more pericyte coverage of tumor blood vessels and intratumoral T cell infiltration could be detected. This indicates that the expression level of cGAS plays an important role in the process of tumor cGAS-mediated tumor suppression, vascular normalization, and anti-tumor immune response.
Figure: Tumor cGAS mediates anti-tumor immune responses in a cGAS expression-dependent manner
Then, the researchers further evaluated the role of host STING in it. The researchers found that compared with WT mice injected with parental cells, mice implanted with Cgas-deficient cells had significantly smaller tumors, but mice with Sting gene deficiency (Sting-/-) implanted with Cgas-deficient cells had tumor sizes similar to those of the parental generation. Therefore, it can be seen that the anti-tumor effect induced by tumor cGAS depends on host STING.
Interestingly, the tumor suppression, vascular normalization, and anti-tumor immune response mediated by host STING also depend on tumor cGAS. Specifically, circulating tumor-reactive lymphocytes (cTRL) formed similar tumor burdens in Sting-/- mice and WT mice, but Cgas-deficient cells grew faster in Sting-/- mice.
The above findings together indicate that tumor cell cGAS and host cell STING regulate tumor vascular remodeling and anti-tumor immune response in a mutually dependent manner.
Figure: Tumor cell cGAS and host cell STING function interdependently.
Vitamin C: Activating TET2 to Enhance Anti-Tumor Effects
After further mechanism analysis, the researchers found a key link in the anti-tumor effect—the tumor suppressor TET2.
After overexpressing the tumor suppressor genes Tet1, Tet2, and Tet3 in liver cancer cells, it was found that compared with Tet1 and Tet3, overexpression of Tet2 significantly increased Cgas expression at both the transcript and protein levels, and even enhanced Cgas enzyme activity.
Therefore, it can be determined that TET2 is the main mediator of cGAS expression in liver cancer.
Mechanistically, the pathway by which TET2 exerts its function is not complicated. Specifically, the tumor suppressor TET2 collaborates with the IL-2/STAT5A signaling pathway to upregulate the expression of cGAS in liver tumors and produce cGAMP; subsequently, cGAMP is transported to vascular endothelial cells through the LRRC8C channel, activating STING in endothelial cells, thereby enhancing the recruitment and transendothelial migration of T lymphocytes.
However, in hepatocellular carcinoma, the expression of the tumor suppressor gene TET2 is significantly reduced. If there is a way to enhance TETs activity, maybe the anti-tumor effect can be restored?! The researchers thought of the "once popular" vitamin C and immediately put it into practice.
Excitingly, in vitro experiments showed that VC treatment greatly induced the expression of cGAS in liver cancer cells at both the transcriptional and protein levels. A similar situation was also observed in mouse experiments. After VC treatment, the expression of cGAS in mouse tumors was significantly upregulated, which was consistent with the in vitro results.
In fact, vitamin C can not only activate tumor cGAS through the leakage of cytoplasmic dsDNA but also increase tumor cGAS expression through TET2-dependent epigenetic modification of DNA demethylation, which can be described as "double-pronged". After upregulating the level of tumor cGAS, the cGAS-STING pathway in endothelial cells is activated, thereby promoting the migration of lymphocytes.
When mice were treated with high-dose VC (intraperitoneal injection of 4g/kg), CD31+ tumor blood vessels decreased and intratumoral hypoxia occurred, but the α-SMA+ envelope coverage of CD31+ tumor blood vessels and intratumoral CD8+ T cell infiltration increased significantly. In addition, after VC treatment, the downstream IFNβ and ISGs activated by STING, vascular stability genes, and adhesion molecules related to endothelial-lymphocyte interaction were significantly upregulated.
Therefore, vitamin C treatment can induce tumor vascular normalization and improve immune infiltration in liver cancer. Moreover, the researchers further evaluated the effect of VC combination therapy in cancer mice receiving anti-PD-1/PD-L1 treatment and found that when VC and anti-PD-L1 combination therapy was carried out, it could effectively enhance the original anti-tumor efficacy.
To sum up, supplementing vitamin C can effectively activate the tumor suppressor gene TET2, induce the normalization of tumor blood vessels, thereby enhancing the immune effect of anti-tumor treatment, and provide a strategy for enhancing the efficacy of combined immunotherapy for liver cancer.