Ioane forms part of a back three including Toulouse wing Ange Capuozzo and Zebre full-back Mirko Belloni.
Fresh from scoring a hat-trick of tries for Stade Francais in Saturday's 43-24 Top 14 victory over La Rochelle, hooker Giacomo Nicotera will captain the side for just the second time.
Alongside him in the front row, Simone Ferrari will pack down at tighthead, with Muhamed Hasa at loosehead.
Ferrari and replacement back Tommaso Allan are the only two players in the matchday 23 who played in the Azzurri's only ever victory over the Springboks in 19 previous attempts, a 20-18 success in Florence 10 years ago.
Paolo Odogwu joins Leonardo Marin in the centres in the absence of the injured Tommaso Menoncello and Juan Ignacio Brex.
Quesada is missing 16 players, including captain Michele Lamaro and other key forwards Sebastian Negri and Andrea Zambonin.
Quesada said he would not use that as an excuse, even though opposing coach Rassie Erasmus had picked a powerful South Africa team.
"I think it's a massive show of respect of Rassie and his staff, knowing that they have a short week next week before playing France... knowing that he puts his best team, the best players in the world," said Quesada.
"All of us are very proud of that, and at the same time preparing for it.
"We are trying to make sure we present ourselves on Saturday, even with a lot of changes.
"At the same time it's a nice opportunity one year before the World Cup to see new players who've never played, some players who have been out of the team for a couple of years are back, to test our character to see how we react to this."
Samuele Locatelli will make his debut at openside flanker in place of Lamaro with Alessandro Ortombina, who will make only his third appearance, at blindside.
Experienced pair Federico Ruzza and Niccolo Cannone will form the second row, while Lorenzo Cannone starts at No.8.
The match will be played in Turin, where a year ago, the world champions won 32-14 despite playing most of the match with 14 players after Franco Mostert's early red card.
Nations Championship 2026
The inaugural Nations Championship will see six northern hemisphere and six southern hemisphere nations battle it out across six rounds in the July and November international windows before assembling in Twickenham for one unforgettable finals weekend on November 27-29.
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Italy team:
Starters: 15-Mirko Belloni; 14-Ange Capuozzo, 13-Paolo Odogwu, 12-Leonardo Marin, 11-Monty Ioane; 10-Paolo Garbisi, 9-Alessandro Fusco; 8-Lorenzo Cannone, 7-Samuele Locatelli, 6-Alessandro Ortombina; 5-Federico Ruzza, 4-Niccolo Cannone; 3-Simone Ferrari, 2-Giacomo Nicotera (capt), 1-Muhamed Hasa
Replacements: 16-Tommaso Di Bartolomeo, 17-Danilo Fischetti, 18-Ion Neculai, 19-Enoch Opoku Gyamfi, 20-Ross Vintcent, 21-Manuel Zuliani, 22-Stephen Varney, 23-Tommaso Allan
South Africa team:
Starters: 15-Damian Willemse, 14-Kurt-Lee Arendse, 13-Jesse Kriel, 12-Damian de Allende, 11-Ethan Hooker, 10-Sacha Feinberg-Mngomezulu, 9-Morné van den Berg, 8-Jasper Wiese, 7-Pieter-Steph du Toit, 6-Siya Kolisi (c), 5-Ruan Nortjé, 4-Salmaan Moerat, 3-Thomas du Toit, 2-Malcolm Marx, 1-Ox Nché
Replacements: 16-Jan-Hendrik Wessels, 17-Gerhard Steenekamp, 18-Wilco Louw, 19-Lood de Jager, 20-Cameron Hanekom, 21-Paul de Villiers, 22-Grant Williams, 23-Manie Libbok
