Always play Very Hard.
I only use VATS as a 'ohgodsurprisebumrush!' panic button, try hard not to use it otherwise. I find the real-time combat, especially in closer quarters even w/guns, adds difficulty plus imo is way more fun than "pause, select target, unpause, watch slo-mo animation.'
Doesn't make it more difficult, but for immersion I find turning off dialogue subtitles helps me. Otherwise I can read so much faster than they can talk that I impatiently click-click-click past their voices. Forcing myself to listen to them because of no text titles helps me to pay attention to what they're saying and notice any vocal inflections/emotions and thus my immersion. Of course, you can still click-click out even so, if you want, like for the boring common npc bits. The actual dialogue choice-options still show, just the npc-spoken lines don't.
Sometimes I use my mod that alters XP gains and level-gain speed via mods. I don't want or need to be lvl30 to finish the game and I like staying low-mid level (under 15) for majority of the game anyway. It hasn't made combat much harder, but it does limit skill-check/perks a lot, which changes the way I play.
Don't buy anything from the shops. Including ammo.
Try a "dead is dead" playthrough, meaning if you die in the game, it's game over, no reloading your save, you can only start a new character. That's about as hardcoe as you can get while self-gimping. =p
Ironman! (meaning no shops either)... I used to do those in action-rpg's like Diablo, but I have such a hard time with the discipline of actually self-deleting a chr. if it dies.