It's going to be about the afterlife. Hell, they've already covered aliens... How do you top extraterrestrials? I can guarantee mortality will be the motif.
Now for setting, I suspect something Egyptian. The Lost Ark was in Egypt, but the Ancient Egyptian culture is ripe for Indy. Perhaps the founding of Israel? It could be about Jewish/Christian mythology, too, but that's already been played in two of the movies. Maybe undead things?!? I'm going to maybe surmise there will be a sacrifice or even a zombification of the hero. Maybe that's a reach...
I definitely know things that it won't do: dinosaurs, killer sharks, friendly aliens, the Holocaust (see a theme here?)
My educated guesses:
- Indiana Jones and the Afterlife
- Indiana Jones and the Cult of Osiris
- Indiana Jones and the Land of the Dead
- Indiana Jones and the Torment of the Undead
- Indiana Jones and the Spectre of the Tomb
- Indiana Jones and the Tomb of the Messiah
- Indiana Jones and the Mortal Coil
- Indiana Jones and the Deathly Hallows
- Indiana Jones Meets the Grim Reaper!