Mauricio Pochettino has confirmed - at a press conference covered by the club's official Twitter account - that Ryan Mason, Mousa Dembele, Nabil Bentaleb and Alex Pritchard will all miss Tottenham Hotspur's game against Manchester City this weekend.
There were hopes that the quartet would make it back to fitness in time for Saturday's Premier League fixture, but Pochettino has ruled them all out.
The absence of Mason, Bentaleb and Dembele leaves Spurs short of options in central midfield, and should mean that Eric Dier and Dele Alli's partnership will continue.
Dier and Alli were excellent in Tottenham's most recent top-flight outing, against Crystal Palace, but they will be severely tested if picked to start against City.
Pritchard, meanwhile, will be eager to make it off the treatment table - as he is yet to have an opportunity to impress this season.
The youngster was expected to break into Spurs' team this campaign, after impressing on loan at Brentford during the 2014/15 season, but his progress has been halted by injury problems, and his only appearance this term came as a late substitute against Everton.
With Spurs without a full strength squad from which to select, their game against City looks to be a huge test, but the Lilywhites are unbeaten in the league since opening day, so they should be in confident mood.