So this is an area i have struggled with too. I have an older 300 which I love and can feed either a 2X12 cab wired in stereo with Eminence speakers or a pair of Peavey PA speakers. I use the full amp models in Studio Direct in order to get the modeling of both the preamp and power amp section of the amp I am choosing in the POD (IMHO). The 300 does have some slight coloration and the reactance mimics tube compression to a degree but it will never replace the modeled characteristics of the power section in the POD. It is not a guitar amp power section so I do not try to run Stack or Combo outputs to it, they sound like crap to me except going to my DT 25.
I do like to change the cab sims though. Going to the PA (FR) speakers I always use a cab sim though I may experiment with different cabs and mics for slight tonal variations. Going to the guitar cab I usually use no cab sim as the cabs own real world action is great. I don't want to add another simulation of a cab's performance on top of the actual performance of my cab. I can use EQ to change the tone if I want or need. I also run the stereo signal through an ADC equalizer before the 300 for global EQ when necessary. I find that more effective and easier to dial in than taking up an extra block in my patches and it works across all my banks wherever I am.
I also have the DT25HD and I run it into either one or two of my 2X12 cabs. I connect with the L6 link. For my ears I much prefer the preamp models with no cab selected. The full amp models and even the cab settings change the tone enough that I begin to hear the dreaded fizz. I don't get that with the pre's and no cab. The tone is a little fatter and a little less presence but I can EQ if I need it. I really like the tone of my cabs anyways. If I had a combo it might be different since Line 6 designed it to use the cab sims and when you use the DT without a POD, there is cab simulation by default.
Since you are using a 4X12 guitar cab, it will not act like a FR cab. It has it's own color, feel, reactance, whatever... You may want to see what your tones are like with out the POD cab sim. Let your own cab do the work. Take some time to build set lists with various combinations, full, pre, cab, no cab etc... with no other effects and just listen to them and see what you like as you switch back and forth. Even the guitar you use makes a difference. It's your gear and ears and no matter what we think about ours, you have to find what works for you! Most of all have fun doing it...