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I played league well over ten years ago.  I quit when they removed the Crystal Scar game mode, as that's when it became clear to me that the people front-running league had no interest in what the players found fun or enjoyable, but only wanted to curate the play experience to funnel people toward the professional e-sport scene.  The revelations about the exploitative work environment and shady backroom deals with oppressive governments, like saudi arabia, only cemented my conviction about not returning.
I tended to enjoy playing Trundle or Sion in Jungle, as I really enjoy playing tanky controllers in most of my gaming experiences.  City of Heroes / City of Villains was the game I probably sank the most hours into my whole life, and found loads of enjoyment as Controllers, Masterminds, Brutes, and Tankers.  But then again, I enjoyed pretty much all of City's Archetypes, other than the Peacebringer/Warshade.  Those were just too finicky for me, personally.

Let me see if I can recall how I progressed through NXF.
I started with Earthquake Hellfire on a corner, and focused on the Slow effect, building up some Chips for extra damage before I really understood what I was doing.  In other words; just sort of experimenting, but knowing how useful Slow effects are in other Tower Defense games, I figured it would probably be good here too.
I focused my initial builds on self-buff and AoE Skills.  I quickly found that the AoE Skills were my primary bread-and-butter, and I'd use them judiciously to get large groups of enemies defeated or at least weakened enough for my towers or auto-attack to finish off.
I can't remember if I was able to get the first boss on my first attempt, but I definitely remember losing to the second boss until I switched up my build to include Axe Throw instead of the attack-speed buff.
I've experiemented with all 4 Tower types, but find that the most effective layout is a couple of Earthquake Hellfires, and a bunch of Firestarters next to them set up at the initial start of the path and corners.
I didn't realize how to equipt inventory items until my 5th to 7th play session, but once I did, I started to do much better.  I now have Epics for Helmet, Pants, Gloves, Weapon, Shield, Necklace, both Earrings, and both Rings.  Rare Armour and Boots.  And a Destructor with +39 Damage and +0.26%, and a Tarrasque with +59 HP, +17 Armour, and +28 Magic Resist.
Before I got a powerful inventory loadout, I beat the level 3 and level 4 bosses by building Towers at the start of the path, then selling them and rebuilding them again incrementally.  It didn't always work, but eventually managed to pull it off.

An Endless Mode could be enjoyable, mayhaps, where Boss enemies show up mixed in with regular enemies every 10 Waves or so.

My biggest concern currently is that the map is HUGE, but ends up being a lot of wasted space, since there usually aren't enough enemies to generate enough Matter to build elaborate layouts.  I think it was Bloons 3 that had a really good balance for amount of resources-versus-length-of-game.  By the time a player gets to the final Wave before Endless mode, they'd usually have raised enough money to build dozens of monkey towers.  It might be handy for you to explore the Bloons games for some ideas on how to structure costs and rewards for the pacing you'd like to have in NXF.

I'm still experimenting with the Permanent Skill system and am only at level 27, but will give you my thoughts once I've gotten further along in it.

Did you have any particular questions or areas you wanted me to focus play-testing and feedback on?