Dante and Vergil aren't immortal that's for sure, even if they can survive a lot.
In the Devil May Cry novel Gilver said that if he cuts out Dante's heart, he wouldn't be able to recover, no matter how much demon blood runs through his veins.
I have to point out that the novel is semi-canon, but I guess this statement has a hint of truth. Hideki Kamiya also said that the heart is the most important, so this might be the case, even more that Vergil was "dead" when Mundus removed his human heart.

I also think that their regenerative abilities have their limits when they are exhausted.
About Sparda; it seems that he didn't die completely, honestly it's hard to tell, because in Nico's reports it is written that Sparda sealed himself~ this isn't quite equal to death, although I can't really tell, because every source says differently.

Moreover, we've seen many times that Vergil and Dante were stabbed in the chest with a sword and nothing serious happened to them, but "cutting out" and "stabbing" can have a completely different effect on them and maybe they can't regenerate after that, but who really knows, with them everything is possible, we can only speculate about how and who can kill them.

Apart from that, unfortunately I don't remember Dante's statement from DMC4 that you are referring to, but I assume he meant about human strong fighting spirit and strong will, or rather all the traits that distinguish humans from demons and that give humans an advantage over them.

Originally posted by WhiteAngel7:

Dante and Vergil aren't immortal that's for sure, even if they can survive a lot.
In the Devil May Cry novel Gilver said that if he cuts out Dante's heart, he wouldn't be able to recover, no matter how much demon blood runs through his veins.
I have to point out that the novel is semi-canon, but I guess this statement has a hint of truth. Hideki Kamiya also said that the heart is the most important, so this might be the case, even more that Vergil was "dead" when Mundus removed his human heart.

I also think that their regenerative abilities have their limits when they are exhausted.
About Sparda; it seems that he didn't die completely, honestly it's hard to tell, because in Nico's reports it is written that Sparda sealed himself~ this isn't quite equal to death, although I can't really tell, because every source says differently.

Moreover, we've seen many times that Vergil and Dante were stabbed in the chest with a sword and nothing serious happened to them, but "cutting out" and "stabbing" can have a completely different effect on them and maybe they can't regenerate after that, but who really knows, with them everything is possible, we can only speculate about how and who can kill them.

Apart from that, unfortunately I don't remember Dante's statement from DMC4 that you are referring to, but I assume he meant about human strong fighting spirit and strong will, or rather all the traits that distinguish humans from demons and that give humans an advantage over them.

Damn, I have nothing to add, I like that. Guess Itsuno added things later but didn't change what was introduced with lore. I wonder what's really going on with Sparda now. I had to think for a moment what was going on. Nico report is as a source of information so I believe it. It would be dope to see Sparda in DMC6.

In game ( ͡° ͜ʖ ͡°) But no joking they are hard to kill