Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?

Yeah, that would be friend. Of cancer. Not humans.

Please refer to the preproof of a new article entitled “Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?” to be served up hot and juicy in the International Journal of Biological Macromolecules soon.¹

The article is pretty long, but the message is simple. The authors found that the N1-methylpseudouridine (m1Ψ) - the same one that induces frameshifting - promotes cancer.

Figure 1: Cancer oopsies. Source: A. Rubio-Casillas, D. Cowley, M. Raszek, et al., Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?, International Journal of Biological Macromolecules (2023), https://doi.org/10.1016/j.ijbiomac.2024.131427.

We have found that m1 Ψ from mRNA vaccines impair the RIG-I and toll-like receptor (TLR) signaling pathways, thus blocking IFN Type-I synthesis.

It’s interesting because I very recently wrote an article about the relationship between SARS-2, the CRISPR/Cas-9 system, and HIV. In this article I referenced a study that showed “that the SARS-CoV-2 mRNA product (BNT162b2) activates the RIG-I/TLR–TNF–NFκb axis”. In this most recent study, the authors include a subsection entitled “mRNA vaccination impairs the RIG-I signaling pathway: implications for cancer development”.

THM: RIG-I is a well-studied and important molecule in the pathogen recognition pathway due to its importance in activation of type 1 interferons, antiviral responses and cancer control. You can probably guess what I am thinking.

On RIG-I - retinoic acid-inducible gene I

RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus.²

RIG-I recognizes double-stranded RNA (dsRNA) in the cytoplasms of cells and activates type-1 interferons - pro-inflammatory cytokines (think IFN-γ release) - and antiviral responses. RIG-I is also documented to be associated with certain cancers depending on ‘development’ of immunopathology.³

Of note, in this specific setting, RIG-I activation and type I interferon induction were shown to promote cancer progression.⁴

The above Nature papers were published in 2017 and 2020.

The bottom line here is that I find it hard to believe, once again, that this known pathogen recognition receptor (PRR) RIG-I, that specifically recognizes RNA, that plays known roles in antiviral responses and immunopathologies (including cancer pathologies) if uncontrolled, was not considered as a potential ‘inducer’ of cancer pathologies by means of dysregulation.

“m1Ψ-containing RNA attaches to RIG-I but is unable to trigger the traditional RIG-I conformation changes that are associated with strong innate immune responses”.⁵ What did they think was going to happen since RIG-I impairment has been shown to be associated with certain cancers? Think lack of control of cancer cell proliferation by type-1 IFN pathway disruption.

If TLR signaling is impaired - ie: they cannot ‘see’ due to m1Ψ as per the immune-evadey DESIGN of the modified mRNAs - then how can adequate anti-tumor responses be mounted? They can’t.

We were warned.⁶⁷

The authors mention the frameshifting issue and also the IgG4 issue which is also linked to cancer: “We suggest that increased IgG4 production derived from repetitive mRNA vaccination could induce cancer development in susceptible individuals”.

Amazingly, they also talk about G4 quadruplex and R-loop formation.

The article is exceedingly thorough, and points out what they call unexpected results with regard to the m1Ψ sub-ins. I don’t know man. Anything exogenous, that interferes with/plays-on known immune system function is going to have downstream effects. Potentially: unpredictable. Even though the unmodified products didn’t have these effects as per this review, I personally would anticipate absolutely anything to occur when exogenous genetic material is injected into cells: expect the unexpected.

As the authors correctly point out, cancer is complex. It’s a metabolic disorder inherently-linked to hypoxic environments and imbalances in our cells and bodies. The modified mRNA shots are absolutely experimental in every way a product can be. I find it impossible to fathom that anyone might not have expected bad outcomes - even if you forget about the fact that the LNPs themselves are exceedingly problematic. Cancer is maintained by our inherent systems - if you perturb these systems - you run the risk of letting the cancer… be more cancery.

Maybe I am just an ‘assume the worst’ kind of scientist, but, when you’re talking about genetic material, viruses and cancer, shouldn’t everyone be like this? Shouldn’t the regulators have been like this? Shouldn’t they - at the very least - be talking about this now??

All-in-all, an excellent and terrifying review. Lots of information. Read it.

1. A. Rubio-Casillas, D. Cowley, M. Raszek, et al., Review: N1-methyl-pseudouridine (m1Ψ): Friend or foe of cancer?, International Journal of Biological Macromolecules (2023), https://doi.org/10.1016/j.ijbiomac.2024.131427

2. https://en.wikipedia.org/wiki/RIG-I

3. Nabet, B. Y. et al. Exosome RNA unshielding couples stromal activation to pattern recognition receptor signaling in cancer. Cell 170, 352–366.e13 (2017)

4. Rehwinkel, J., Gack, M.U. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol 20, 537–551 (2020). https://doi.org/10.1038/s41577-020-0288-3

5. Durbin, A.F., C. Wang, J. Marcotrigiano, et al., RNAs containing modified nucleotides fail to trigger RIG -I conformational changes for innate immune signaling. MBio, 2016. 7(5): p. 10.1128/mbio. 00833 -16

6. Pepini, T., A. -M. Pulichino, T. Carsillo, et al., Induction of an IFN -mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design. The journal of immunology, 2017. 198(10): p. 4012 -4024

7. Seneff, S., G. Nigh, A.M. Kyriakopoulos, et al., Innate immune suppression by SARS - CoV-2 mRNA vaccinations: The role of G -quadruplexes, exosomes, and MicroRNAs. Food and Chemical Toxicology, 2022. 164: p. 113008