Poor Tomoko. The fact that she can't communicate with other people is quite depressing. All the more so if it's her own fault.
Pretty much the entire show can be considered this since it's about Tomoko desperately trying (and continually failing hard) to be more socially adept.
The ending of chapter 27 (or episode 10 of the anime). Tomoko is shown starting a club of her own and bonding with her schoolmates... and then it's revealed that it was all in her imagination, her proposal for a club got rejected by the school council and she's sitting alone in her room, having tea with her plushies and retreating into her fantasies. A What If? omake makes it even worse by having her proposal approved by the school council, and then showing Tomoko one year later: sitting uncomfortably in the corner of her own club while other club members are having fun together, too shy and awkward to strike up a conversation with them or agree to their invitation to lunch, and regretting starting the club in the first place. Either way, she can't win.
Chapter 40: Tomoko reads manga in class and imagines people coming up to her to ask what she's reading, then eats snacks to get people to come up to her and ask if they can share. It doesn't work of course, as usual, but the difference this time is the utterly broken expression on her face (not to mention the '[REDACTED]' thought bubble). Eventually the teacher calls her into the staff room to tell her she should make some friends; the teacher's been watching her all week and has noticed that Tomoko's not OK. Just the acknowledgement that Tomoko's having problems makes it all a lot more real somehow.
The scene where after she begins running to school in a positive mood, she ends up vomiting in an alley. This scene is specially painful in the manga.
Her relationship with her mother. Sometimes Tomoko just lashes out at her, and she promptly lashes back.
The panties as tissue scene. It can be seen as funny, or as a teenage girl having a serious freakout.
Yuu and Komiyama also pass through social isolation and feel excluded because of their otaku tendencies. They both also were shy and awkward in middle school.
Simultaneously with Tomoko, Komiyama hid from Yuu that she styled her hair from an anime and was also badmouthed because of it.
Although Yuu has become popular, she hides many of the things that she likes from her group and only feels at ease to share them with Tomoko.
In chapter 46, the reveal that she and Komiyama never started a good friendship in middle school. The very next chapter effectively destroys any chances of the two becoming friends in high school in foreseeable future as well.
Said event also indicates just how far Tomoko's inability to understand other people goes and how easily she links everything to sex, to the point where it's clear that she is her own worst enemy at ever developing relationships with others.
In the first chapter of the spin-off Yuu asks Tomoko whether she has any nicknames given to her by others. All that Tomoko can recall are various insults.
Tomoko crying herself to sleep because she's so "happy" is already sad enough, but her brother's complete and utter lack of empathy for her in the next room really drives it home. She's alone even in her own home.
One of the few times a person does a random act of kindness for Tomoko — a boy buys a new umbrella for her when her umbrella is broken and she's stranded in the rain — she cannot appreciate because she's asleep when it happens. And she never realizes what happened when she wakes up and finds the umbrella. It's pretty depressing that for her it's more plausible to think that her umbrella somehow fixed itself than the idea that someone could have done that for her.
And even though in a later episode she meets up with one of the those guys, who mentions this. She screws up any chance of having a meaningful friendship by using him to try to impress Kii-chan.
Tomoko and her brother don't get along at all. Every time they speak, Tomoki would rather be doing anything other than spend time with her. In some scenes, it almost seems like Tomoki actually despises her. But old videos and childhood souvenirs show that when they were small children, they spent virtually every waking moment together, playing games, enjoying life, and utterly idolizing each other. They didn't even have their tired eyebags then. To see their loving relationship turned into something toxic and strained really is heartbreaking.
And as the manga shows, it's really Tomoko's fault, as she grew obnoxious as she got older. And while she is quick to note her own shortcomings, this doesn't extend to realizing just how her behavior can annoy her brother.
Coincidentally, their eye bags start developing at around the same time.
In Omake 7, when she tries to offer up her seat to a hot guy with a broken leg. After fumbling and getting flustered, she ends up, alone, in an unfamiliar train station, with noone to talk to for the next 30 minutes. And then she realizes she forgot her bag of otaku goods.
When Yuu contacts Tomoko via mobile phone for the first time, she starts wondering why hers has started to shake until she realizes it is a simple call. Tomoko has forgotten how her own phone works because nobody has ever bothered to call her , it is funny and extremely sad at the same time.
Later on in the anime, we get a look at her contacts: all she has is her family and Yuu.
The scene of Tomoko with the two guys at a bus station during heavy rain. Tomoko is so nervous she starts sweating a lot and even tries to make a (bad) joke about it. It's stomach-cringingly awkward but also kind of really sad to see...
Chapter 37 of the manga, when Tomoko manages to have a normal conversation with a similarly friendless senior on her last day as a first-year student and his last day of high school. If they had spoken to each other sooner, maybe they both could have made a friend. And then there's the possibility that Tomoko will graduate just as excluded and alone as him.
Chapter 23, where Tomoko realizes she forgot her textbook and, since it's too late to skip class, thinks of being invisible for the duration of it. She gets found out almost immediately and reprimanded by the teacher for not asking a friend to let her borrow a textbook or the person next to her. Same chapter, she gets reprimanded by a random stranger cause she's apparently a bit too close to the banister of a waterway. It doesn't help that Tomoko herself cries during both those times.
The fact that these kinds of thing can happen in real life, where some people experience crippling amounts of social anxiety whether in the form of a learning or mental disability like Autism or Agoraphobia or whether the person is just naturally unable to make friends. Given that humans are social animals, social isolation can easily become a crippling and debilitating situation where a person can wither away from a combination of psychological issues stemming from their lack of social ability.