England boss Eddie Jones says he has "drawn a bit of a line in the sand" after shaking up his squad for a training camp later this month.
Billy and Mako Vunipola, Jamie George and George Ford are among the big names left out of the 45-man squad.
Eight uncapped players are named while there are nine others included who made their debuts in the summer.
"We are selecting now with the 2023 World Cup in mind," Jones told BBC Sport.
Jones says the door is far from closed on the players left out, but says they need to "work out if they want to give it all for the next World Cup".
He added: "It is not the end of the road. It is an opportunity for them to refresh, re-energise and re-focus. We will see how they go."
However, as was the case halfway through the last World Cup cycle, Jones has started the process of revamping his squad.
'Opportunity is there for Smith'
Ford's exclusion paves the way for Marcus Smith, who made his England debut in the summer before being called into the British and Irish Lions squad in South Africa, to get an extended run at fly-half this autumn.
"He has a glint in his eye and wants to get better, he did well for us in the summer and the opportunity is there for him," Jones said of the 22-year-old Harlequins playmaker.
Along with Smith, Leicester's highly rated full-back Freddie Steward, as well as Alex Dombrandt, Joe Heyes, Lewis Ludlow, Adam Radwan and Harry Randall, are all selected having won a first cap in July.
Newcastle's Radwan, who scored a hat-trick on debut against Canada, continued to catch the eye with a handful of startling moments in the Falcons' season opener against Harlequins on Sunday.
"He could beat you in a phone booth couldn't he, he is super quick," Jones said.
"He is going to be head-to-head with Jonny May and it is a great battle there. Two lightning-quick wingers who are potentially competing against each other or who could potentially fill the two spots."
'He doesn't sound Australian! Lynagh wins call-up'
Another winger, Harlequins' Louis Lynagh, is rewarded for his sparkling end-of-season form as Quins won the Premiership title, with a place in the 45-man group.
The son of Wallaby great Michael, Lynagh qualifies for England, Italy and Australia and followed up his two tries in the Premiership final with another couple against Newcastle.
"I've been impressed by his acceleration. I rang him up yesterday and said 'mate, you don't sound like an Australian!'" Jones joked.
"He said 'I know, I have to work on my Australian accent a bit!'
"I played against his father - his father was obviously a brilliant player - and he has got some of those characteristics, he has that strength around his hips to drive through tacklers. It's a good opportunity for him."
Also among the eight uncapped players is the 31-year-old Gloucester centre Mark Atkinson, who is rewarded for years of excellence in the midfield at Kingsholm.
"Some players, like a Mark Wilson, who have been in the club system for a while, they fight hard and they come into Test rugby and have a great period of time," Jones explained.
As well as Lynagh and Atkinson, the other uncapped players are Harlequins flanker Jack Kenningham, Wasps hooker Gabriel Oghre, Sale scrum-half Raffi Quirke, Harlequins hooker Sam Riley, Sale prop Bevan Rodd and Northampton back Ollie Sleightholme.
An experienced core does remain though, with Test centurion Ben Youngs named as one of the scrum-halves, while Lions tourist Sam Simmonds is included despite not playing for England since 2018.
Prop Joe Marler, who has won 72 caps, is also back in the fold having not featured in the 2021 Six Nations.
"You take Joe on face value, he is one of the most honest players I have met," Jones said.
"We had a chat about six or eight weeks ago and he wants to give it a go. At this stage he is fully committed and we will see where we can take it because he was in wonderful form for Harlequins at the end of the season."
This mini camp at the end of September forms part of England's preparation for the November internationals, with Tonga, Australia and South Africa the opposition in consecutive weekends at Twickenham.
"The squad is that intoxicating mix [of youth and experience]. The thing that keeps on improving you is competition. We have tried to create a very competitive squad that is going to push each other and get every bit of talent out of each other.
"That is the opportunity for this group of 45 players."
England's 45-man squad
Forwards: Jamie Blamire (Newcastle), Callum Chick (Newcastle), Luke Cowan-Dickie (Exeter), Tom Curry (Sale), Trevor Davison (Newcastle), Alex Dombrandt (Harlequins), Charlie Ewels (Bath), Ellis Genge (Leicester), Joe Heyes (Leicester), Jonny Hill (Exeter), Ted Hill (Worcester), Maro Itoje (Saracens), Jack Kenningham (Harlequins), Courtney Lawes (Northampton), Lewis Ludlam (Northampton), Lewis Ludlow (Gloucester), Joe Marler (Harlequins), George Martin (Leicester), Beno Obano (Bath), Gabriel Oghre (Wasps), Sam Riley (Harlequins), Bevan Rodd (Sale), Sam Simmonds (Exeter), Kyle Sinckler (Bristol), Will Stuart (Bath), Sam Underhill (Bath).
Backs: Mark Atkinson (Gloucester), Owen Farrell (Saracens), George Furbank (Northampton), Ollie Lawrence (Worcester), Louis Lynagh (Harlequins), Max Malins (Saracens), Joe Marchant (Harlequins), Jonny May (Gloucester), Raffi Quirke (Sale), Adam Radwan (Newcastle), Harry Randall (Bristol), Dan Robson (Wasps), Henry Slade (Exeter), Ollie Sleightholme (Northampton), Marcus Smith (Harlequins), Freddie Steward (Leicester), Manu Tuilagi (Sale), Anthony Watson (Bath), Ben Youngs (Leicester).