I have potentially found another therapy that FTO inhibition...

I have potentially found another therapy that FTO inhibition could improve the efficacy of. Below is a section from an article released on the 4th of March. I won't go into too much detail, but the article was evaluating the impact of immune checkpoint-inhibitors therapy in urinary bladder cancer (1). Now, the article does not mention FTO overexpression directly, so I am required to make some connections with other studies that I have discussed here with you.

For starters, two articles released this year (January 2021) report that FTO is overexpressed in urothelial carcinoma cells from xenographs obtained from bladder cancer patients (2,3). They found that FTO overexpression was linked with bladder cancer cell growth and proliferation. Another study evaluating released in March 2021 evaluating the influence of m6A methylation (addition of a methyl group) on cancer growth and metastasis via macrophage reprogramming (4). What the article found was that METTL3 depletion (which does a similar thing to FTO overexpression) led to increases in M1-like and M2-like tumor-associated macrophages (TAMs), which led to promoting tumor growth and metastasis. Also, the study found that METTL3 depletion (FTO overexpression) contributed to the immune checkpoint anti-PD1 therapy resistance.

Ok, so to summarize the above. FTO is overexpressed in bladder cancer cells which increases tumor growth and proliferation. The mechanism of FTO overexpression is linked with macrophage reprogramming, increasing M1/M2-like TAMs, that promote tumor growth, metastasis, and resistance to immune checkpoint therapy.

Now, the new article released on the 4th of March was commenting on Bacillus Calmette-Guerin (BCG) Intravesical therapy, which is one of the most widely used immunotherapies in bladder cancer. One of the functions is to stimulate, trigger, and activate the immune system, developing tissue macrophage resistance. So, resisting the increased expression of M1 macrophages likely due to FTO overexpression which can be seen above. As metioned in the screenshot below, resistance and influence of tumor microenvironment are major factors that influence the effectiveness of BCG therapy.



I strongly believe that more evidence is required to further substantiate whether FTO inhibition would improve sensitivity to BCG therapy. However, I also think that making connections and assumptions like this are important aspects of science. Hence, I am very curious as to the influence of FTO inhibition on immune checkpoint-inhibitor therapies in bladder cancers as well as other cancers.

1. https://www.mdpi.com/2673-7523/1/1/2
2. https://www.aging-us.com/article/202359/pdf
3. https://onlinelibrary.wiley.com/doi/pdf/10.1002/ctm2.310
4. https://www.nature.com/articles/s41467-021-21514-8