How do!
Spinning off from my other thread, in which I postulated that if the Imperium could defeat one of it's myriad foes, comprehensively and permanently, the others might well follow suit.
Simple reasoning behind this is that the Imperium is currently fighting an extended holding action. It has the numbers, technology, ships, firepower etc to crush absolutely any foe, but right now cannot properly bring it's massive, ponderous weight to bear on any one foe.
Main stumbling point is just how far flung the Imperium is. Orks are everywhere, Eldar can appears nigh on anywhere, Nids insist on popping up where you least expect them, Necrons could be on any planet, regardless of it's present state. Chaos - cults are a constant threat (destablise the right planet, destabilise the region). About the only one that isn't an omni-present pain in the posterior would the Tau Empire!
But what if, deus ex machina reasons, the Imperium utterly crushed a single foe to the point where it couldn't come back. How would that affect the dynamics of the ongoing galactic wars?
For instance, it would appear that Craftworld Eldar are the most vulnerable to a slight case of genocide. Whilst they could certainly put up a fight, not only do they lack numbers in the general sense, but their Craftworld based nature leaves them relatively expose, and hard to reinforce. To my mind, they're definitely one foe the Imperium could, given the right opportunity, extinguish for ever. Given their generally capricious nature, and ability to use the Webway to attack without warning, this would seem a major boon......
BUT....they're also crucial to the ongoing war against Chaos. Without Farseers generally interfering, even when it's not in otherwise Imperial affairs, just how much leeway would that grant the various forces of Chaos? Would the forced extinction of Craftworld Eldar be more of an own goal in the grand scheme of things?
So hopefully, you get the gist of it. Remember, we're working from the assumption, however improbable/impossible it actually is, that the Imperium could get it's act together enough to entirely wipe out a single foe!