There are those who would probably argue he's pretty much useless as-is, but think about this one. What if this man who had traversed two-thirds of the world that's underwater suddenly found himself stuck on the other third? What incredible underwater beauty and mystery has he seen, and now would never find again?
For this "fish out of water" story (sorry, couldn't resist), he would become this adventurer similar to Indiana Jones, trying to explore this world he had always shunned while always looking for a way to return to the oceans he loves.
Let him lose his power by magical means or something. I think there's a wealth of possibilities here for the character.
After decades of being the toughest of the tough, what would happen if he suddenly found himself normal again? It's easy to be courageous when you know your skin is impervious to bullets and death rays. Now imagine how hard it would be for him to suddenly realize he has limitations and can no longer "tough" his way out of everything?
I can see this easily being a powerful storyline if done right. In the beginning he might feel useless or even a little scared because he feels useless as a normal guy. Then he eventually starts to realize true courage isn't in being able to stand up to a dozen blazing bullets without harm, but it's being able to stand up to the man behind the gun and saying you will not cower even if he could kill you.
How could he lose his powers? The treatment that gave him his iron hard skin begins to wear off. Imagine that first panel when he is shot and suddenly realizes he has a bullet wound. Very powerful!
Turning him powerless would have to involve either making him human or forcing him to stay alien without any abilities.
I've honestly never understood DC's love for this character, but they continue to make him a linchpin of the DC universe. With the guy constantly having to come to terms with who he is and wants to be, let's take away his powers. He can be the "thinker" of the JLA (even though I know he's not involved with them after the DC reboot).
Robbed of his mental abilities and super strength, would he feel valuable to a team anymore? It would give the character the chance to move beyond his past and concentrate on his future. Let him find a place among his team mates as a leader. And hey, it's not like the character isn't kind of limited enough as is. Fire as a weakness? Bummer.
The thing that makes Deadpool such a funny comic is the fact that he's completely reckless in everything he does because he knows he'll heal up no matter what happens. Get shot in the head? It's cool. Lose an arm? Be patient and it'll be back. But what would he be like if he suddenly knew he wouldn't heal back from a wound?
I think he'd be pretty much a coward for a while. A funny coward, but a coward nonetheless. Then his need for mayhem and money would overwhelm his cowardice and he'd be forced to go on a mission of some sort.
At that point he couldn't be crazy reckless anymore. He'd be skittish and have to be forced into a confrontation. When the bullets started flying or the ninjas started coming, he'd have to change tactics to win. It would allow us to explore a new side to the character while still giving him room to make wisecracks and be his hilarious self.