Linus Pauling was a fearsomely great scientist who is remembered by the general public for his advocacy of megadoses of Vitamin C, a favorite topic of his later in life. Infectious disease, cancer: Pauling advised gram amounts of ascorbic acid and had a lot of theorizing to offer about why that was beneficial. So while his scientific legacy is (among other things) his work on chemical bonding, on genetically-based disease and the concept of molecular biology in general, and plenty of lesser-known deeds such as encouraging the earliest NMR studies of organic compounds, his legacy in the wider world involves increased vitamin sales and the association of Vitamin C in particular with the treatment of disease.

Unfortunately, Pauling’s ideas about how Vitamin C would prevent and treat disease were wrong. Instead of having an antioxidant effect (which is one of the things he proposed and what most people associate with it), at very high doses ascorbic acid has a pro-oxidant mechanism of action (see below). This is almost entirely seen with i.v. dosing, and it’s worth noting that Pauling’s 1976 paper on prolongation of life in terminal cancer patients via ascorbate supplementation used a combination of oral and i.v. routes. Attempts to follow up on this observation (mostly with oral dosing) did not reproduce the effect, and it’s become clear that if you’re going to see anything, it’s via intravenous administration, and at even higher doses than Pauling thought.

Here’s a new paper from a team in Italy that suggests that these effects have to do with immuno-oncology, and that the combination of i.v. ascorbate and immunomodulators might be quite useful. Vitamin C only showed effects in mouse tumor models when the animals had a fully competent immune system. Narrowing down, its beneficial effects appear to depend on T-cell pathways: antibodies to CD4 or CD8, for example, took things back to baseline tumor development. But on the other hand, the combination of Vitamin C with anti-PD1 and/or anti-CTLA-4 antibodies was noticeably more effective. This appears to be independent of the pro-oxidative damage mechanism mentioned above, as well as of the reported effects of high-dose ascorbate on iron metabolism.

The big question is, does this apply to humans? It should be easy enough to find out, and such trials are the only way we’re going to know. Even in the mouse models, there were some tumor lines that responded strongly to this treatment, and some that were refractory. And as the authors note, they saw a benefit from Vitamin C alone in the mice, which is much harder to show in human patients and suggests that they could still be a disconnect. So the relevance to human therapy (as is so often the case in oncology) will only be made clear by treating actual humans. The authors suggest trials with escalating doses of ascorbate in the first few rounds of immune checkpoint therapy, across several different tumor types, with comparison to immuno-oncology standard of care. High-dose i.v. ascorbate treatment of this sort has been shown to be well tolerated; there should be few barriers to trying this out. If it works, it would be a low-cost way to increase the efficacy of several existing therapies – the results will be very interesting indeed. Good luck to those trying it, and to all of us by extension.

But if this work makes some headlines of the “Linus Pauling was right” sort, don’t believe them. Pauling was right about a lot of things, but like many bold scientific thinkers, when he was wrong he was wrong in grand fashion. And he was wrong about vitamin C and cancer. None of his hypotheses about any therapeutic effects have turned out to be correct, and the main mechanistic thing that does seem to be happening is the exact opposite of what he would have predicted. Huge doses of ascorbic acid are a precursor to hydrogen peroxide formation inside the cell, and at high enough levels this can overcome the natural antioxidant defenses. There are many lines of evidence for this, but if you’d tried to sell Pauling on the idea he might have kicked you down the stairs.