The Lilywhites will welcome Japhet Tanganga back from suspension this week, and the defender could displace Emerson Royal at right-back, but Matt Doherty will also be eyeing a start against his old employers.
Davinson Sanchez, Joe Rodon and Ben Davies are all in line to replace Eric Dier, Cristian Romero and Sergio Reguilon at the back, while Hugo Lloris should be granted a rest as Pierluigi Gollini starts in goal.
Tanguy Ndombele is finally being handed some long-awaited opportunities under Santo and could once again start as part of a midfield three with two fresh faces in Oliver Skipp and Harry Winks, with Dele Alli and Pierre-Emile Hojbjerg possibly dropping out.
As a result, Bryan Gil could feature out wide as Giovani Lo Celso makes way after a rare start at the weekend, while Harry Kane will seek to improve on his record of one goal from his last four encounters with Wolves.
Tottenham possible starting lineup: Gollini; Tanganga, Sanchez, Rodon, Davies; Winks, Skipp, Ndombele; Gil, Kane, Son