> Barring a major engineering challenge in in-orbit propellant transfer
We already have that challenge. Last I checked, SpaceX was claiming it would take five Starship launches to store enough fuel in the depot to perform one lunar mission (which is innately strange considering Apollo did it in one launch on a less powerful rocket, but that's not even the point here). But according to NASA, SpaceX has failed to adequately account for cryogenic boil-off in their plans, meaning that they expect it will take about twenty Starship launches per lunar mission. That's not exactly inspiring, especially given what it implies about the number of launches it would take to get to Mars and back. To solve the cryogenic boil-off issue we might need to switch to different fuels entirely, which would necessitate new engines.
We already have that challenge. Last I checked, SpaceX was claiming it would take five Starship launches to store enough fuel in the depot to perform one lunar mission (which is innately strange considering Apollo did it in one launch on a less powerful rocket, but that's not even the point here). But according to NASA, SpaceX has failed to adequately account for cryogenic boil-off in their plans, meaning that they expect it will take about twenty Starship launches per lunar mission. That's not exactly inspiring, especially given what it implies about the number of launches it would take to get to Mars and back. To solve the cryogenic boil-off issue we might need to switch to different fuels entirely, which would necessitate new engines.