A current thread on RPGnet posits that comedy RPGs are particularly difficult, which I haven’t found. The third RPG I ever ran was TOON, and it was the first one that really clicked (due to its light rules that supported the genre) and I ran Ghostbusters on and off for a couple of years - at one point also running a TOON parody of it every month or so for the same players, for ideas that were a bit too weird.
Ghostbusters has quite a lot of what is being discussed - weird situations played straight with the main characters providing most of the humour. It could work as a straight action-horror movie (with a redesign on Slimer and a different "form of the Destructor") but the characters’ response to it moves it into comedy. However, the adventures for the Ghostbusters game mostly involve comedic situations because it can’t guarantee you’ll have Bill Murray at the gaming table. It plays a bit lighter than the movie by default, more like The Real Ghostbusters cartoon.
Humour in the book and in adventure ideas is the easiest way to make a comedy game work, giving the GM something to work with rather than relying on the table for all the laughs.
But if the table will provide the laughs, go for it. While running TWH for years, following the model of Buffy, only a couple adventures every season run from a comedic situation - the archaeological dig for an episode of Time Team unearthing ancient evil, going behind the scenes of the TV show we were supposedly creating, a typical apocalypse cult being totally incompetent - while the majority were straight urban fantasy plainclothes superheroics where the funny arose from the dialogue. The main tools in the setting’s comedy portfolio are the PCs’ genre awareness and their ability to backtalk and joke about life in-character. Most players will do a bit of this anyway, but the Buffyverse is a setting where a snarky response to a monster’s threat can naturally be delivered by the character rather than kept to player table talk. Most sessions, all I did to create humour as a GM was join in with bantering NPCs and provide the occasional villainous feed line.