The game begins with the MSPA Reader trying to escape Doc Scratch's place after seeing that Spades Slick has arrived and will soon set fire to everything. They go through the fenestrated wall ready to return to all their friends on Alternia, only for the other end to stop working, leaving them stranded. And then, when they gain the Retcon powers from the white logo they discover, they lose their memories.
The fact that they haven't even fully lost their memories. There are things that are familiar to them for reasons they don't know or understand, the main one being the hoodie they're wearing, which they don't know why they have, but have a powerful desire to not let go of.
In Volume 1, the MSPA Reader accidentally loses John's copy of Sburb when they retrieve the mail for him, only to panic when Dad shows up. John gets upset that now he can't play the game with his friends, and mentions that he often feels lonely and doesn't really have any other friends.
Dave also gets upset at not being able to play the game despite having previously claimed that he didn't care that much about it. He's sad that his gift for John was lost as well.
If the Reader suggests hanging out with John in the yard, they'll eventually end up telling him about how they get their powers, and mention that they've died many times before realizing that can't be true. When John wants to know more about these powers, they demonstrate by taking him back in time by a week. However, this also happens to be the time that adult John from the Meat part of The Homestuck Epilogues took the 16-year-old kids back to before preparing to fight Caliborn. Present John witnesses this, and though he can't hear most of the conversation, realizes that this is an adult version of him, and some of those figures are his friends. When the Reader takes him back to the present, he says he needs some time alone to think about it, leading to one of the bad endings.
Volume 3 makes it clear how bad Dave's life is. He tells the MSPA Reader that he's often on guard for anything that could happen at any moment, only for it not to happen after all. He also has to wash clothes in the shower either because he can't use the washing machine, or because he doesn't have one at all, and doesn't seem to be able to keep food and drink in the fridge either.
Dave's first bad ending has him get stressed over the possibility of liking John when he'd previously thought he was straight. It says a lot about what he was brought up to believe.
In his second bad ending, the Reader brings up how out of the ordinary his living situation is and he tries to deny it. When the Reader thinks they've lost their chance at befriending him, they think they can make it better by teleporting him to somewhere safe, only for Bro to show up and throw them out of the window as they're about to do it.
Even the good ending is rather sad. The Reader lets Dave think of anywhere he would like to go and their teleportation will take them there. They end up at an Olive Garden, where Dave is happy about getting to eat their free breadsticks. Word of God even confirmed that he doesn't get to eat much at home.
In Volume 4, Jade threatens the MSPA Reader with a gun, thinking that they ruined her and the other kid's chances of playing Sburb on purpose, and tells them that she no longer dreams on Prospit or gets messages from the Trolls. She becomes friendlier when the Reader tells them it was an accident, but eventually gets angry at them again because she feels like she no longer has a destiny, and then hides in her bed, crying.
Jade says that she's been very lonely on the island with only Bec to keep her company, and that she was looking forward to playing Sburb because then that would all change. She also mentions that her Grandpa did a lot of travelling and never took her with him. Joey and Jude weren't the only ones he neglected.
When the Reader tries to teleport Jade away from the island, Bec immediately teleports them back. Jade says she knew that would happen, and shows the Reader that she'd tried setting the transportalizers to take her away from the island, only for Bec to stop her.
Jade and the MSPA Reader find their way into the temple, and end up on Prospit when they use one of the transportalizers there. Jade is excited at first, but then the guards won't let her see the Queen. Then she and the Reader are forced to leave when the place gets under attack, and it's implied that Prospit was destroyed after they left, leaving them unable to go back.
Karkat's route in Volume 5 shows just what he has to struggle with as a mutantblood. He has an early warning system that deliberately warns him when someone is approaching his hive. When he claws the MSPA Reader's arm, and they show him the blood, his first reaction is horrified panic, immediately thinking he somehow got cut, exposing his mutant blood color to what he thinks is a blueblood, and that it's all over for him. He even stops the Reader from leaving, and willingly shows them his blood color by cutting his hand and saying how they can't leave because "it isn't safe for people like us", and at one point a drone appears in the neighborhood and he takes himself and the Reader into a hole to hide, where he panics about what is currently happening.
If the Reader stays with Karkat when they're hiding from the drone, it will find them anyway, resulting in his hive being burned down, his lusus dying trying to save him, and him being on the drone's list of trolls to cull immediately. Anywhere the Reader teleports him to, they show up. Even worse, he realises that the drone discovered them specifically because they were hiding together, and blames the Reader for it before leaving and implies that he doesn't like to get too close to people in case anything like this happens, and it's very likely that the drones will soon find him and cull him.
The first place they teleport to after escaping the hive is just outside of Sollux's place. Karkat's messages with him reveal that he knows about his blood colour, and he tells Karkat to come inside to try to protect him while he figures out a way out of this. Karkat refuses, not wanting Sollux to get killed too. He even starts to cry.
Kanaya's route shows us what would happen if she were to become Matesprits with Vriska - if the MSPA Reader tries to help her, Kanaya will message Vriska and the two will enter a relationship. Kanaya is happy at first, but when the Reader zaps a few days ahead, they find that the relationship has become toxic, and Kanaya breaks up with her before telling the Reader that it's their fault she's now unhappy. The ending card even shows her crying.
Vriska's route shows us what Vriska's life is like past the persona of the cool badass she puts on, a miserable existence where she's constantly forced to kill other kids to avoid her lusus's wrath, a lusus who is constantly inside her head screaming to feed her, and while she tries to have fun during the FLARP campaigns it's very clear when we see the actual feeding part that she hates every second of it and is a miserable broken shell of a girl, most of her friends have left her, the few friends she has left she has very rocky relationships with, so she has very little support to help her through this emotionally, and that's all before you take into account that she is still a child, and has been doing this for a while meaning it's very likely her first kill was before she was even the equivalent of ten years old.
At the beginning of Vriska's route, the MSPA Reader gets grossed out by the grubs used to play the game, and if they decide to leave, the ending card shows Vriska looking sad, as if she really wanted to play with them.