I am a huge fan of set piece battles. It's one of the reasons a minis/grid-centric combat doesn't entirely do it for me. Here's my take:
How do you use giant setpieces/improvisational environment deathtraps, in an RPG?
Treat the encounter something like a Rube Goldberg device, where each component is some mini-challenge (a skill check, an attack roll, whatever). The Obsidian skill challenge rules should work pretty well for 4e games, with each attempt being part of the machine. If you know where it needs to end, you can introduce a large number of prerequisite steps before you reach that point.
How do you let the players know "You simply cannot use your equipment/abilities alone to best this threat" before they TPK? Or "You need the Macguffin to beat this thing"?
How do you telegraph to the players that things in the environment or the macguffin can be used to best the enemy, without straight out saying, "Use This Thing"?
What's wrong with saying "Use This Thing?" I mean, even without metagaming: "You realize that no mortal could possibly pierce this hide. You'll need something bigger (Skill check to determine if I can give them a hint)." Or "NPC #3 says 'The legend says that only the MacGuffin can cut off the head of the monster!' "
And what rules do you use, when you do it?
Mostly just concept, not rules.
Envision the encounter itself like a dungeon.
The players want to get from Point A to Point B, and as they move toward point B, obstacles present themselves. Individual obstacles in this kind of battle are generally skill checks, or even entire skill challenges. Attack bonus and power selection matters less than a good Athletics or Acrobatics bonus. In 4e, pay for failures in healing surges to represent a sort of "long-term endurance." Also make certain successes cost surges: "You win, but at a cost."
Sometimes, they need to make a choice of direction. They'll come to a room with three exits in a dungeon; they'll come to a point where they might have three different possible ideas in fighting this beast. Maybe two of them are wrong and will lead simply to harder challenges and more lost surges. Maybe all three are wrong because they took a wrong turn back three decisions ago. Maybe all three are right, just one will be easier than the others (or lead to a bigger reward if successful).
Thinking about the encounter as a whole like this allows you to make it the focal point of the game. You might want to make some of the challenges combats instead of skill challenges, especially in 4e, so that people can feel like they're contributing something unique to the goal, but combats shouldn't be too hard to work in: a fight vs. the cultists loyal to the monster, or a fight vs. a piece of the monster itself (a single tentacle as a solo monster, or something that monster spawns, or even an encounter against the beast that ends with it or the PC's fleeing).