If you find pollution is not a challenge, try a deathworld run. If you can already beat a normal deathworld - turn down trees/moisture, turn up pollution diffusion ratio; then you can add rampant, armored biters, bob's enemies, etc. I recommend the infinite ore patches mod as well, you will be defending the starter patch for a veeery long time.

My favourite recent challenge was "New Game +", you start with all tech (perhaps except damage upgrades) unlocked, but biters also start at 1.0 evolution. You technically don't need any science to launch a rocket, but you still have to figure out how to build a mall (and enough defences) before triggering a single attack.

Factorio is an excellent tower defense game!