Vitamin D has been reported to inhibit cancer cell growth, promote cell death, reduce angiogenesis in tumors, and reduce the pro-oncogenic activity of tumor-associated fibroblasts. Although some studies have found that higher vitamin D levels are associated with reduced incidence or mortality from several cancers, the exact effects of vitamin D on cancer development and its interactions with the immune system and microbiota are still not fully understood.
Vitamin D exists in two special forms - D2 and D3, which are transformed into active forms in two "workshops" - the liver and the kidneys. Once activated, they act like magic keys, binding to vitamin D receptors in the body to activate and adjust gene expression.
While all this is happening, Gc globulin plays an important role. It binds to the metabolic products of vitamin D, storing it in the blood. Studies have shown that mice lacking Gc proteins exhibit significant immune-dependent resistance against specific melanoma cell lines. These mice controlled tumor growth more effectively and accumulated more activated CD4+ and CD8+ T cells in their tumors than control mice with normal Gc protein levels. In addition, Gc-deficient mice also showed stronger responses to commonly used immune checkpoint blockade therapies, such as anti-PD-1 and anti-CTLA-4 treatments.

When mice lacking the Gc protein lived together with normal mice, the normal mice also learned how to resist tumors, as if this resistance could be passed on through living together. Through further experiments, the researchers found that this resistance was actually related to the microbes in the mice's guts. More interestingly, by transplanting feces from mice lacking Gc protein into normal mice, the tumor resistance of the normal mice was also improved.
So, the researchers explored the relationship between vitamin D and intestinal microbes. They found that even if the intake of vitamin D was increased, if the mice were sterile (i.e., without intestinal microbes), their tumor resistance did not improve. This suggests that simply increasing the intake of vitamin D3 does not directly enhance the resistance of mice to tumors, especially when these mice lack key immune cell types such as T cells, B cells, or certain immune signaling molecules.
It turns out that vitamin D acts through the vitamin D receptor (VDR) of intestinal epithelial cells to regulate gene expression, thereby affecting the physiological state of the host. By performing metagenomic analysis of mouse fecal samples, the study determined the diversity and composition differences of intestinal microbes under different vitamin D levels and genetic backgrounds. The study found that increased vitamin D levels promoted the growth of Gram-negative bacteria and inhibited the growth of Prevotella, and this change was associated with enhanced tumor resistance. Through oral gavage experiments, the study confirmed that Gram-negative bacteria can enhance the resistance of mice to tumors, but this effect requires sufficient vitamin D levels to achieve.
Overall, this study shows that the interaction between vitamin D, the gut microbiota, and the immune system is important for cancer immunity. Although vitamin D itself has limited direct effects on tumor resistance, it promotes the immune system's resistance to cancer by affecting the composition of the gut microbiota, and this effect can be transferred to other mice through fecal transplantation.