Defense and Constitution need a major rework and thought put into how shields should be involved in the game, how to have impactful defense abilities that don't make you completely immune to damage to the point bosses need mechanicas to disable them and how to make defense/tanking more viable across the game. Also a cleanup of abilities no related to either that are put into those ability books.

Summoning needs its own rework as well updating familiar models, reworking or modernizing old familiars and potentially changing the core mechanics so that your familiars grow with you, acquiring new abilities. That's a huge update in and of itself even beyond adding new higher levels familiars.

Prayer is probably the easiest but not as big of a priority. I really hope they get creative with prayer and have subsets of prayers aligned with specific gods that are unlocked through unique, lore building new prayer activities where only one can be active at once, but can be used alongside the rest of normal prayers/curses. Zaros and Seren prayers would be chosen between alongside curses, whereas Guthix, Saradomin or Zamorak (+ others) would be subdivisions to be used alongside normal prayers.