The biggest factor would be if the existing parties at some point fail to absorb a political movement in substantial form that thus requires it to go outside of the existing tents, but that typically just reshuffles the deck chairs and you end up with a new party system with one of the old ones splitting between the new party and the older former competition (basically what happened in the 1850s).
What stops that from happening now is that national parties' apparati have become very good at finding new sources of discontent, buying them out, and astroturfing the whole thing.
Republicans have been very good at assimilating new movements but Democrats still think new movements need them more than the Democrats need the new movements.
This just isn't really true. The Democratic coalition has changed just as substantially as the Republicans have over the contemporary era. Just look at how much the Democrats have zoomed left on issues like the environment, immigration and censorship since the 1980s.
The U.S. will never have a major third party because the GOP and Democrats are big and diffuse enough to morph their coalitions into whatever they need to do in order to win.