Wigan Warriors pair Sam Tomkins and Sean O'Loughlin will miss the rest of the Super League season and are doubts for England ahead of the Four Nations.
Full-back Tomkins, 27, has a foot injury that requires surgery to see the extent of the damage, while captain O'Loughlin, 33, has a calf problem.
Both players will miss Friday's play-off semi-final with Hull FC and then a potential Grand Final on 8 October.
England host the Four Nations tournament starting in late October.
Forward O'Loughlin suffered his latest injury setback on Friday, hurting his calf in the warm-up before the win against Catalans Dragons that secured a home semi-final against Hull FC.
"Wigan have only 20 players available from a squad of 35 but there is a tremendous spirit and confidence amongst this group that thrives in adversity," said chairman Ian Lenagan.
"Despite all of the challenges that the club have faced this year I, head coach Shaun Wane and the squad believe that we can defy the odds to make this an excellent season end."
The Four Nations, in which England face Scotland, New Zealand and Australia over a three-week period, starts on 28 October.