There is really only one reason why any broadcast TV show is canceled - poor ratings. It’s very unusual for a popular show to be turned down - although there are exceptions (e.g. gents of SHIELD.
Beyond the lack of people tuning in, there are other factors why the Marvel Cinematic Universe spinoff was frustrating to casual viewers, especially those who are fans of the movies or the streaming shows (e.g. Runaways, Daredevil, and The Defenders).
Ignoring The Movies
Agents of SHIELD didn't really ignore the Marvel Cinematic Universe - there were tie-ins to Thor: The Dark World, Avengers: The Age of Ultron, and the fall of SHIELD in Captain America: Winter Soldier; even Nick Fury and Asgardian warrior Sif made an appearance. But ever since The Snap, as Agents of Shield left the confines of Earth, fans have been asking if the show is canon or not.
More importantly, for the Agents of SHIELD producers, in of ratings - shouldn't they take advantage of the fact that the show is set in the same “universe” as two of the highest-grossing movies of all time?
Villain Envy
They say superheroes are only as good as their villains, which is certainly true in the comics and on the big screen; but Agents of SHIELD is a serial on the small screen, and using the same villain over and over would become tiresome (e.g. Lost in Space, Deep Space Nine).
Nonetheless, Agents of SHIELD has suffered from a lack of compelling bad guys that have populated the Marvel movies, such as Loki, Thanos, Hela, and even Ronan the Acc. Unfortunately, the list of great TV sci-fi/superhero villains - Kingpin, Negan, the Penguin, the Borg - doesn't include anyone from Agents of SHIELD.
Absent Father
Joss Whedon is the creator of successful movies like Toy Story and the first two Dollhouse - but not this time. Although listed as Executive Producer for Agents of SHIELD and the writer of one episode, his fingerprints seem to be lacking in the production.
Agents of SHIELD carries Whedon’s self-referential wit and fun superhero moments, but its often imposed with little emotional payoff. It's not unusual for episodic television to lack an overall plan - or have it thrown out because of the fall of SHIELD in this case - but viewers had hoped there would be overarching emotional satisfaction at the end of each season, instead of clever cliffhangers.
Aliens of Shield
After six seasons of Agents of SHIELD, our heroes have encountered a number of alien races in their travels - the Kree, Chronicoms, the Inhumans (more or less), and various Lighthouse inhabitants. Coupled with the rise of Gravitron, Hive, the Ghost Rider, and other superhuman characters, it's hard to know which threat is more pressing.
Assuming MCU Bad Guys are still out there - Thanos, mischievous Asgardians, the Kree (again) - there’s a veritable banquet of super antagonism every week. From a plotting perspective, it begs the same question that Spider-Man fans often ask about the Sinister Six - what happens if more than one of these miscreants was to attack the Agents of SHIELD at once?
Favorite Character Changes
In episodic sci-fi shows, characters rarely stay the same, so why does it seem so forced in Agents of SHIELD? Over the course of six seasons, square-jawed Grant Ward has become rewritten as a Hydra villain (and Hive), Phil Coulson has been repeatedly remolded, and Melinda May has alternatively betrayed or fallen for Coulson.
The pairing of Fitz/Simmons has evolved (devolved?) from light comedy and explanatory jargon to bitter scientists and would-be killers in recent seasons. Good storytelling mandates that characters need to be continually developed, but it’s hard for the casual fan to see these changes as anything but self-serving.
Ghost Rider Redux
In what now seems like a blatant attempt to create a spin-off, Agents of SHIELD introduced and then discarded Ghost Rider, one of the most revered and misconstrued heroes in comic books. Ghost Rider first appeared as stunt driver Johnny Blaze in his own comic in 1972 and was famously brought to life by Nicholas Cage in Ghost Rider in 2007.
In Agents of SHIELD, Ghost Rider (Gabriel Luna) was introduced at the start of season 4 and carried over eight episodes dealing with Inhumans and the evolution of Quake, and then mostly forgotten as the show moved on to LMDs and other shiny objects. You can add Ghost Rider to the pile of compelling and popular superheroes abandoned by Agents of SHIELD.
Risk-Reward for Disney
Agents of SHIELD has survived in a pop-culture environment that saw Marvel’s movies conquer the box office, and Disney’s Netflix and Hulu series rise and fall as the studio pivoted to their forthcoming Disney+ productions. Whatever benefit the show had to the Marvel brand (e.g. promoting movies, keeping beloved characters alive, driving merchandise sales, etc.) has dwindled outside of hard-core fans.
If your free-to-watch show doesn't reach a wide range of people, from an ing viewpoint, you might as well cut and run, or perhaps move to your fledging streaming service, which makes money directly via subscriptions.
Unbound Sci-Fi
Agents of SHIELD and its critics seemed to have embraced the show's ability to traverse genres as much as it travels through space and time. The Marvel Cinematic Universe that birthed the show is certainly boundless as well, but it isn't mercilessly reinventing itself like this show.
Agents of SHIELD has covered outer-space, time-travel, shapeshifters, magic, robotics (LMD), the Framework, and so-on. When the story palette is unlimited, anything can happen, and that’s not always a good thing. Especially after season 5, some people have labeled Agents of SHIELD being rather zany.
Agent Coulson … Again
Good storytelling means putting your protagonists into conflict, versus each other, an antagonist, or even an untenable solution. For an action/adventure series like Agents of SHIELD, viewers need the sense that the characters may face incredible challenges - otherwise, the risks are too low for anyone to care.
This is difficult to achieve, for casual and ardent fans alike, when your main character, Agent Phil Coulson, is repeatedly resurrected. What’s at risk for Coulson, and by proxy everyone he interacts with (e.g. Fitz, also brought back to life) if they are indefatigable? Maybe Agents of SHIELD would still be alive if they let their main character die.