Question: Would it ever be possible to make a fungus mutant that can take over a mammal body?

Hannah Blyth answered on 13 Jan 2025:

The short answer is that it is highly improbable that someone (or perhaps even nature without hundreds of millions of years) could mutate a fungus to take over a living mammal’s body. Mutating a fungus to achieve these abilities would require massive changes to its genome (and the knowledge of what changes to make) and would likely be too stressful for the fungus to survive. Some fungi can cause severe diseases in immunocompromised humans; these infections do not involve control over the host’s body.

Some context:
Fungi and mammals have been around one another for hundreds of millions of years, with fungi diverging from animals around 1–1.5 billion years ago (Fun fact: humans and animals are technically more closely related to fungi than plants).
It is unlikely that a fungus will evolve the ability to take over a LIVING mammal’s body due to significant biological barriers. Mammals, including humans, are naturally resistant to most fungal infections because of their warm body temperatures and advanced immune systems. These things together create an environment that most fungi cannot tolerate, so it would be just as tricky to mutate a fungus towards that.
Behavioural manipulation like the Cordyceps fungus infecting living ants (which inspired the Last of Us plot) would be much more challenging in the complex mammal nervous systems compared to the relatively simple insect system, which took millions of years of co-evolution (and in researching for this answer, is a plant fossil possibly capturing the evidence of this fungus infecting ant hosts 48 million years ago!).