This is not so much a suggestion as a thought experiment exploring the ways a game like KSP2 could make some of the ideas from real-world ISRU into a fun, playable experience. There are a few essential principles in this, to my mind, in this order of priority: fun gameplay, efficient mechanics, and allusions to real life physics. Im going to focus on the 2nd, as I think it's the hardest part and mitigates the other two. Its important to realize in this that real-life will always be much, much too complicated to emulate exactly and be fun, and given how complex KSP1's basic framework is its critical that colonization not utterly dominate player time. So the question for me is how few resources and processing steps are necessary to convey the idea of ISRU? Fuels, Parts, and Life Support
Starting with fuels we have some guesses: Methalox, Monoprop, Xenon, Uranium, He3, MH, And likely H2 and Antimatter. From a purely chemical standpoint the raw materials for these are relatively few: Hydrogen, Oxygen, Carbon, Xenon, Helium-3, and Uranium. But from a harvesting standpoint even these can be simplified. From my perspective H2O and CO2 could be gathered together from the surface as "Ices", Xenon and O2 could be extracted directly from some atmospheres, He3 from surface regolith, and Uranium from mining. Thats only 3 basic resources: Ore, Regolith, and Gasses, which could then be processed into CH4, O2, H2O2, Xe, U, He3, and H2 and further into MH and Antimatter with the appropriate processors. Each of the 3 basic resources could be scanned and understood with values from low to high, which would only effect the rate at which they could be harvested. Or it could be that concentrations for things like He3 and Ices are displayed independently in scans, but this might make it more complicated to harvest raw regolith and process it later and know what you're going to get.
Next come Parts, and I'll include both rocket parts and colony modules in this. Again to me this about maximizing simplicity while creating good gameplay, and fortunately I think real life does us some favors here. Im going to simplify the raw materials for most parts as Metals, Uranium, and Plastics. I say this because I think both Metals and Uranium could be produced from Ore, and Plastics could be produced from Regolith as an analog to either ethylene or basalt fibre. The reason for the latter distinction is it would cause players to consider both high-quality Ore and Regolith concentrations when picking colony and mining sites, or come up with ways to transport and combine them. Again Ore could have a single concentration rating and be separated using different processors, or Metals and Uranium could have their own individual concentrations depending on the location.
Last is LS. Now, I understand many players trepidation at this topic, but I think there are ways to make this both manageable and fun. Given understandable concerns about players time-warping and accidentally killing whole colonies I think there are 2 ways to approach LS as a resource.
1: LS would be an engrained requirement for increasing crews and populations. In order to add more crew to a large vessel or take advantage of population booms you would need to add Hab modules that increase max crew capacities. We could assume onboard systems are closed loop and that LS is a static resource necessary only for building new habitable modules. In that way it would be just like Metals or Plastics as a part cost, but would instead be produced with greenhouses or MELiSSA style regenerative LS modules fed with Ice rich regolith and nutrients from Ore.
2: LS would be a resource thats consumed over time, but the consequences for running out would be relatively minor. It could be created by greenhouses, extended by recyclers, and made indefinite with regenerators. You'd need to pump it around just like any fuel, and you'd be inclined to make sure you have enough on any vessel without a regenerator, but if you ran out it would only make Kerbals Grumpy and less productive, not dead. Using an overall vessel-wide Happiness rating could also encourage players to add other more luxurious habitation modules like centrifuges and recreation facilities and diversify the kinds of later-game modules you'd want to add to growing colonies.
That would lead to a resource flow that looked roughly like this:
Ore> Metals, Uranium
Regolith> Plastics, Methalox, Monoprop, He3, H2, MH, Antimatter
Gasses> Xenon, O2
And the following processors:
Refinery > Metals
Enrichment Centrifuge > Uranium
Polymator > Plastics
Fuel Processor > Methane, Oxygen
Monoprop Processor > Monoprop
He3 Factory > He3
Electrolyzer > H2
Metalic Hydrogen Foundry > MH
Antimatter Plant > Boomsauce
Greenhouse > LS
None of which sounds crazy overwhelming, but I think is just enough to get players thinking carefully about surface concentrations as they're developing and expanding their capabilities.