May I humbly propose that you’re asking the wrong stuff.
All of those questions have an answer in art. You want to protect castles? You paint castles. You wanna protect treasure and gems? You paint treasure and gems. You want goblins to attack? You get the picture. Ultimately, the only thing differentiating you from any other tower defense game remains that art. And there’s no telling people will like your artstyle or topic in general.
What you need to differentiate yourself by gameplay. If you have a good idea that sets you apart from the rest, people will play it even if it’s generic like robots, unrelated like zombies and plants, or even completely bonkers like apes and baloons. Though the baloons were a stroke of genius in the sense that they allowed that fantastically satisfying plop sound.
Instead, ask yourself what new gameplay you can bring to the table. Plants vs. Zombies was fun because you had 5 paths instead of just one and you had to manage your resources between those lines. Robo defense, like that warcraft mod I can’t remember, was fun because you had no predetermined path at all, and the player created the path by placing his turrets on the field. Gemcraft was fun because you upgraded your towers by gathering and combining your gems into more powerful ones instead of just buying them.
So make the gameplay fun before you make your art nice.
Have the player manage a whole town that has a weaponsmith that produces weapons you can use for your turrets to defend said town.
Have the player craft the turrets out of components himself.
Have the player produce fighters instead of turrets, so they run onto the field and fight the enemies.
Have the units move on a chess board in the fashion chess figures would. Only melee fight, if you can’t get to the enemy, you can’t attack it.
Have the enemies run through toxic gas or a randomly generated minefield, with the player only being able to place walls to divert the enemies path and slow them down.
Once you have a fun idea, the genre presents itself automatically like the town or the chess figures. You still can change the topic to something you might find easier to paint. Some people paint the most amazing dragons, but can’t draw a car to save their lives. Or you can indeed just go for something random. Atoms, microbes, bugs, coins, office supplies, teddy bears, plants, furniture, creatures, vehicles, houses, planets, galaxies. Have microbes infect a human. Give the player soap, deodorant, shower. Have pensils attack and stab a teddy bear. Have bugs steal cars. Prevent pencils from drawing on walls, by distracting them with canvases. Have bugs infest houses. Have planets try to escape their orbit and keep them at bay by upgrading the sun or closeby black holes.
Really, once you have an interesting idea and a dictionary, the question of a “genre”(which really, is tower defense) becomes a non-issue.
