Eternal memes (Longcat, Cockmongler, Pedobear) would probably have to be relegated as late-game summons, or as close-to-final bosses.
NicoRPG's system could work for a 4chan RPG-- it took out the typical RPG element system (fire, ice, etc) and replaced them with moe, The Gay, etc. Konata and Haruhi specialized in weakening enemies against moe, while Abe and Koizumi do the same with The Gay (Abe's Kusomiso Technique could do upwards of 1000 damage).
I'd imagine that could work-- maybe toss in GAR or some such.
Some status effects were also scrapped and replaced (explosive laughter, suicidal fear, Stole The Precious Thing, etc). Same thing could apply-- RAGE, brick-shitting, baaaaaaaw, etc.