Their research led to drugs that release the brakes and constitute "a landmark in our fight against cancer", said the Nobel Assembly of Sweden's Karolinska Institute, which selects winners of the annual prestigious award.
The winners were chosen for "for their discovery of cancer therapy by inhibition of negative immune regulation".
James Allison, from the University of Texas, and Tasuku Honjo, from Kyoto University, despite working in different labs both found that proteins act as brakes on the immune system. Subsequent research has extended this approach to new immune regulatory targets, most prominently PD-1 and PD-L1, with drugs approved to treat certain types and stages of melanoma, lung, kidney, bladder, gastric, liver, cervical, colorectal, and head and neck cancers and Hodgkin's lymphoma.
Honjo, of Kyoto University, discovered a new protein, the ligand PD-1, which also acted as a brake on immune cells.
Commenting on Monday's award, Dan Davis, an immunologist at Britain's University of Manchester, said "this game-changing cancer therapy" has "sparked a revolution in thinking about the many other ways in which the immune system can be harnessed or unleashed to fight cancer and other illnesses".
The American and Japanese researchers worked out what was stopping immune cells from attacking tumors.
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One of Carter's treatments was a drug that blocked the immune-cell "brake" studied by Honjo.
Allison said he remained in "a state of shock" several hours after the news.
Normally, key immune system soldiers called T cells seek out and attack invaders.
Professor Allison, 70, who was in a NY hotel for a scientific meeting, said at a news conference that the Nobel committee evidently had trouble reaching him to break the news - but his phone lit up with a call from his son at 5:30am when the names of the winners were released.
Honjo, who is now 76, told a news conference in Tokyo he was honored to get the Nobel, but that his work was not yet done.
This screenshot shows the official Nobel Prize Twitter account. "After many years of resistance, I think the cancer field has begun to accept immunotherapy now as the fourth pillar-along with radiation, surgery and chemotherapy-of cancer therapy". Their drug showed dramatic success in patients treated in 2012, including giving long-term remission to people with metastatic cancer. But Opdivo became available not long after its development and has proven to be effective, according to Amano. Combinations of the two types can be even more effective. Though this turbocharged immune response can cause side-effects, they aren't usually too serious and the therapy has been hailed as revolutionary for cancer treatment.