The ACT Brumbies pair have come in at first and second-five to replace the injured James O'Connor and Matt Toomua in a backline where the seven players have only five more caps between them than captain Michael Hooper (101) has himself.
The match in Sydney also doubles as the third Bledisloe Cup test between the sides, with the Wallabies needing to win to have any hope of winning the series.
A win for the All Blacks would mean the retain the trophy for an 18th straight year.
Cane said the All Blacks would bring pressure on the Wallabies pair but not because of their inexperience.
"Like any test match we will be looking to put pressure on the guys that drive them around the park," Cane told reporters on a conference call on Friday.
"Their playmakers have been at 10 and 12, so nothing will change. We will look to put them under pressure."
Lolesio and Simone were "quality young footballers", Cane said, adding that players on their debut tend to rise to the occasion rather than let the side down.
"You chuck that Wallabies jersey on and you go out there to put your best foot forward," he said.
"I think most people who make a debut ... have a pretty good game because it is the realisation of a dream."
All Blacks inside centre Jack Goodhue may have a bit of extra sting in his first collision with Simone, who he played with at secondary school in Auckland.
"I think it will be good to have bragging rights over my midfield partner," Goodhue said on Thursday.