Maybe something using AI could be implemented - does a screenshot of your game e.g. every second and if it detects anything that would suggest cheating then it informs some central system and sends it a movie of you playing for the final verdict.
Of course this all is based on the assumption that the local AI can do this fast enough with enough precision.
Well my suggestion is that the local part (which could analyze everything that is happening locally, not only the screen) would be the initial filter and if it detects any hint it takes some data package and sends it to some centralized online system that would provide a final verdict (and ban if needed).
But as you say if it is local then you can essentially run anything on the computer and modify what is ran on it. That basically means it is impossible to make an anti-cheat that is 100% bulletproof aside from something strange like buying a locked-in camera which you need to place behind you as it records everything you do on the PC and then the AI thing happens as I explained.
Maybe for pro play and tournaments that would be acceptable but not for the average player.
Of course this all is based on the assumption that the local AI can do this fast enough with enough precision.