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Dealing a single big threat is easy. Several threats of roughly the same intensity... now those are the empire-killers.

Orks, 'Nids and the Black Crusade may seem the biggest external threats right now. But the Tau are slowly undermining imperial authority in the east, while Dark Eldar raiders and rebellion destroy the Imperium from within, not to mention that technological and societal decay is taking its toll on the Imperium's ability to respond to those menaces.

So I'd say the biggest threat to the IoM is... Themselves. An empire too vast and too complex, besieged by foes within and without.