As we previously reported, Mackey announced he was diagnosed with throat cancer for the 2nd time last August ... after beating the disease in 2001.

We're told the legendary dog musher was in and out of the hospital since June ... with Mackey saying on Facebook in August, "the past several months have been the hardest/worst part."

"Just wanted to say thanks to my friends and family for everything and I love you all so much. I Fully believe it is not my time yet and I’m still doing pretty good but I’m going to have a lot of things to get done in my life."

But, tragically, Mackey died Wednesday night.

Mackey's mother went to FB to break the terrible news ... before Lance's fans filled her comments paying tribute to the champ.

"May the champion musher Rest In Peace," a fan said under the post.

"Thanks for the memories. My sincere condolences to the entire Mackey family and friends. Sadly the world lost a great musher and a even greater person."

Mackey was one of the best in dog sledding ... winning both the 1,000-mile Yukon Quest and the Iditarod Trail Sled Dog race four times between 2005 and 2010. His father and half-brother are also dog mushers.

Mackey was honored by U.S. Senator Lisa Murkowski for his accomplishments and Asteroid 43793 was named after him in 1990 by discoverers Carolyn Shoemaker and David H. Levy.

Mackey is survived by his two children ... whom he shared with his late partner, Jenne Smith, who died in an ATV accident in 2020.