I think the only way to end the Simpsons at this point, considering what a juggernaut it is, is to have a season of final episodes.
As in, have almost a what if thing where different writers get to give their own take on an ending to the Simpsons. Have one where it just ends with Marge taking the kids and leaving, one where Marge is a rabbit, one that explores the methaphysical fuckery of what and where Springfield is exactly. Maybe see if some old names would come back to write a farewell (doubtful). Maybe they could even have a fan submission for one of the episodes, (not one where people vote for obvious reasons but one where one or two of the better submissions gets turned into a full fledged story). And like, have them get weird with it. There are so many talented animators on payroll, and it would be great if they got out and stretched their talents. Maybe like a weird trippy episode that ends with that washed up band bard ODing. No one ending to the Simpsons could be satisfying so why not have multiple?
This is of course assuming they don't develop the technology to automate the voice acting and stuff, meaning so they could go on indefinitely.