Dortmund take on Spurs at Wembley tonight as both teams begin the race to escape Group H, which also features reigning champions Real Madrid and Cypriots APOEL.
However Subotic has fallen ill and was unable to arrive for training on Tuesday while captain Marcel Schmelzer and Marc Bartra were both taken off against Freiburg on Saturday with ankle and groin injuries respectively.
Also likely to miss out are Julian Weigl (ankle), Andre Schurrle (thigh), Sebastian Rode (knock) and Erik Durm (hip), while Raphael Guerreiro and Marco Reus are recovering from foot and knee operations.
“Our long-term injuries are well-known and we have some short-term ones as well,” Dortmund manager Peter Bosz said. “Subotic is sick. Maybe he will come (on Wednesday) but he is not with the group (on Tuesday).”
Watford boss Javi Gracia does not think Abdoulaye Doucoure's form will be affected by his omission from France's latest squad.