The story of the Resident is one- they drank too much the night before and were left behind by every single person they knew. The fact that they're now stuck in an abandoned, uber-hostile environment without anyone they might have known or loved simply because they partied too hard one night is now stuck with them for all time. It's even worse in the planned "solo-only" servers, as the Resident will now have no human contact and might be stuck like that for the rest of their lives.
The fate of the Responders is terribly depressing. They're some of the only good people in the Wasteland, working to rebuild civilization within weeks of the nuclear war rather than years, and we discover they've all been wiped out by disease apparently days before Vault 76 opened. They were the kind of group which protagonists would normally join (and can posthumously) but You Are Too Late.
Averted with the Wastelanders DLC. Coming back to Flatwoods with a stronger, veteran character, one finds a young girl who is wearing a Responder paramedic jumpsuit with her dog. Having learned of the Responders' history and looked up to them, she decided to revive the group as the first new volunteer, staying in Flatwoods to help out anyone that passes through, including new characters fresh out of Vault 76 doing the original main quest. Another girl has gone to the Charleston Fire Department to join the Responders' elite Fire Breathers unit, reviving them as well.
The quest "A Personal Moment", which sees the player tracking down a series of personal journals from the Vault 76 Overseer and learning about her past: she lost her mother to a mining accident and her father to sickness, with her only comfort being her boyfriend, Evan. And then Vault-Tec gave her a choice; she could either marry Evan and be sent to act as Overseer to Vault 101 in Washington D.C. instead, or separate from him and remain as Overseer in her native West Virginia — if she was married, Evan would need a spousal exemption, and Vault 76 already had a slot filled with a civil engineer. The Overseer chose The Needs of the Many — that civil engineer would be useful in wide-scale societal reconstruction after the bombs, whilst Evan was just a miner — but it's obvious from the tapes that it broke her heart that she made that choice. And then she finds that Evan survived the war... as one of the Scorched. Unable to, as she puts it, "kill him again", she locks him in room and begs the player to give him a Mercy Kill.
One particularly sad entry reveals her dad came to visit when she passed her Vault-Tec training despite his illness, and even gave his blessing to Evan. The Overseer mentions her dad wanted to walk her down the aisle, but died only about a month after she passed her training. She than laments how she wished she had gotten to walk down the aisle herself. Take note that Vault 101 is one of the few Vaults to survive unscathed 200 years into the future and this becomes even worse.
"A Personal Moment" isn't the only Tearjerker for the Vault 76 Overseer. If you nuke a target other than the fissures where the Scorchbeasts come from, you'll find a holotape from her outside of the silo that you launched it from, where she chews you out over starting an Appalachian arms race, before begging you to stop this madness, as she still has faith in your fundamental goodness. After that, you can find her final holotape — with what is strongly implied to be her dying words — where she explains she's been injured by a Mole Miner, without any stimpacks or a C.A.M.P to treat her wounds at. Her last words are to chuckle grimly at the irony, when she'd warned you in one of her earlier tapes about this same mistake.
Thankfully averted in the Wastelanders DLC. The overseer is still very much alive, recovered from her mole miner attack, and set up home in Sutton where she can be found doing very well for herself with the support of her own personal Mr. Handy Davenport and keeping an eye on the newcomers to Appalachia to ensure the hostility between the Responders, Raiders, Free States, and Brotherhood of Steel is not repeated when the Scorchbeasts still pose a serious threat. Unfortunately, if you have killed Evan, you have to watch her deal with his fate in person.
The fate of the Overseer in the test Vault below Vault Tech University, he was supposed to be locked in the test Vault for a month to test if his nutrition gruel was a good substitute for normal food, it worked initially, until people started dying from it which caused a rebellion, he tried to contact the school faculty to open the timelocks early but by then the war happened and there was no one to disengage the locks from the outside. In the end the overseer killed himself and the students in the Vault starved from lack of food. The worst part is none of that was the overseers fault, the school headmaster wanted to find out how the occupants of the test Vault deal with extreme stress so he poisoned the gruel and gave them insufficient rations to last the month For Science!
A holotape found at Lost Home in the Cranberry Bog entitled ''Requiem for Kelley'' details two survivors, Parker and Kelley, trying to find shelter. Kelley is severely crippled by radiation sickness, and the two manage to find refuge in a pre-war shantytown. Parker, the fitter of the two, leaves Kelley to scrounge for supplies, and upon finding chems that could save Kelley, rushes back only to find out she's been killed and in the process of being eaten by wild dogs. Even after killing the dogs, Parker regrets leaving Kelley alone to fend for herself and curses the war and himself.
The story of Jesus Sunday and his brother JD, a couple of amateur moonshiners and doomsday preppers who lived through the Great War and temporarily signed up with the Free States movement. Whilst JD threw himself into the group and fell in love with a woman he met there named Briana, Jesus Sunday was scornful of the Free States, as he saw them focused too much on mercy and not enough on fortifying to defend themselves. So he set to stocking up a personal bunker hidden under their cabin — which served them well when the Scorchbeasts leveled the Free States' fort. But Briana and some of the others survived, and then arrived at the Sundays' cabin; JD had told her about it and welcomed them to join. Enraged, Jesus Sunday knocked his brother out cold and then drove them off at gun point. Afterwards, JD would secretly sneak spare supplies out to Briana's group under the cover of hunting trips, but Jesus Sunday found out and confronted him about it. In the fight, JD either fell or was pushed off of a ledge, and died. Then Briana's group found out about it and she led them to attack Jesus Sunday for revenge; he killed them all, but caught a fatal bullet in the process. The last of the five holotapes telling their story is his dying log as he mourns how he just wanted to protect his brother, but wound up killing him.
The fate of Crane in Wastelanders. Crane was the one who discovered and hid the legendary treasure the Settlers and Raiders are both after, and a late game quest involves you trying to figure out just what the hell happened to him as he vanished. Turns out that he had succumbed to the Scorch Plague and stumbled into the Wayward. Duchess, who turns out to have been a good friend of his, couldn't bring herself to kill him even as the Plague drove him to be aggressive, so she instead has him locked in the bar's basement away from those who are hunting him. Eventually, the Resident traces Crane back to the Wayward, and Duchess comes clean and reveals the truth, and the Resident must choose whether to Mercy Kill him or let him continue in his torturous state of existence. Especially sombering in that, unlike pretty much every other Scorched in the game, Crane still retains at least some of his humanity, ranting incoherently about his treasure.