replaying re4r (once again wow get a load of this guy playing resident evil 4 (2023) for the 20th time) and thinking of that little shot of leon looking so devastated right after luis takes his last breath
i like to think that that moment was leon realizing he'd misjudged luis. he'd lumped luis in with the likes of william birkin the moment he heard that luis used to work for umbrella, and he never made an effort to hide the fact that he did not like luis. he was always snapping at him and his flirty little statements, and even tried to interrogate luis a little bit during the section with luis as your companion ('you sure you're just a researcher?")
luis' last words were asking leon if he thought people could change. something leon kinda struggles with throughout the game is that he has an idea of who certain people are in his mind. saddler is predictably unpredictable - he's the villain, so he does villainous things. ashley i would say is also fairly predictable - she wants to go home, so she sticks close to the person who promised to get her there. when it comes to ada, luis, and krauser, leon thinks he knows these people and who they are. he asks ada if she's trying to use him again because it's what he knows her to do. he expects krauser to have a similar mindset to his own and makes comments on krauser not acting like himself because that's probably what he was used to when he was under his command. when it comes to luis, leon thinks he knows that type of person. he's met that type of person before, and he's seen what happens when that type of person loses control. his view of others is very limited to what he knows and it throws him off when what he knows doesn't line up with reality
ada isn't really trying to use leon. she's using the distractions he provides to her advantage, but she's not doing what she did in raccoon city. she responds to his question with a non-answer ("what do you think?"), and if you've played separate ways, then you'd know that she's not really using him. their paths cross, and they help each other, and like i said, she does use the distraction he provides to her advantage at times (and often follows in his wake to let him do all the hard stuff. work smarter, not harder), but it's not the same as what she did in re2. she's willing to let him believe what he wants to, though.
krauser isn't the same man leon knew. he makes that abundantly and explicitly clear. even without the plagas, krauser is filled with hatred and grief for what happened on that mission, and rightfully so. not only did the government abandon his entire team and got them all killed, they then covered up the mission entirely. krauser's actions aren't about getting revenge, like leon thinks. it's about demonstrating his power to those who failed him and his men. he doesn't care about right or wrong, or loyalty, or patriotism, or anything to do with his country. he felt like if he had more power - of any kind - then maybe something could have been different. maybe they could have been rescued, or maybe krauser could have gotten them out himself. los illuminados gave him the power he wanted, and now he wants to show the country that failed him what they created.
luis, from the start, was never the person leon wanted so badly to think he was. if he was, he wouldn't have stayed and fought alongside leon in the cabin. if he was, he wouldn't have tossed the key to leon so he could free himself. if he was, he wouldn't have bothered with making sure leon and ashley (and ada) get rid of the parasites growing inside of them. luis wants to help them because he feels some level of responsibility for them being infected. we know he worked on the research team refining las plagas, and then he betrayed his team and cured himself. the only reason he hasn't cured anyone else is because it wouldn't work. as he dies, luis asks leon if he can be forgiven, if people can change. leon doesn't answer him, but i think in that moment he realized that he was wrong about luis, and i think that sticks with him a lot through the third act of the game.