If we think about this for a second Misty isn't really hindered by anything particularly major which would prevent her return to pokemon series.
Down below ill explain more thoroughly why im of belief how Misty could in reality return at any point if director and writers deem such move as beneficial for anime series:
For start from game perspective in order for her to thrive and move forward character isn't dependant on game features and assets like contests which happens to apply for Dawn or May for example. No; with Misty whole storyline, dreams of becoming water pokemon master and reach heights of other powerful water users(Wallace, Siebold, her rolemodel Lorelei)is anime exclusive. Coming straight from writers head and imagination being able to create tournaments, benchmarks, obstacles and issues she would need to overcome basically in every region and make viable story arc out of it. Like they did with Whirl Cup and Whirl islands archipelago, Orange Islands, Decolora Islands, pokeringers etc.
For that reason alone most suitable time to bring Misty back and provide sequel to story would be in filler arcs taking place after regional league like Battle Frontier was not interfeting with advertizing and allowing writers to tweak around things and use them to their own according to higher level of liberty.
Although implementing Misty in main region could be viable too,
Tying entertainment value with promotional features.Such as playing role with legendary water types like Kyogre was in Hoenn helping to resolve it and advance her understanding for this specie. Enrich on plot introducing experts such as Siebold E4 of water pokemon for example hosting tournaments to represent himself in better light, along with Misty entering them to prove worth and be noticed for her abilities in coming for recommendation for E4 position herself making her top water trainber in world.is first true E4 member using water pokemon.
Also Misty in games isn't tied to any generation as representative of specific saga being gym leader and therefore making it easier to transfer her to any other regions even if she dont exist in games. Since unlike May, Dawn, Hilbert, Leaf, Lucas etc who are main protagonist of certain generation of pokemon and their representatives making people associate that certain generation with them, in gym leaders case there doesnt exist such burden or handicap making i easier to justify their stay. Hence explaining why Brock stayed for so long despite not existing in Ruby, Sapphire or Diamond and Pearl..
Shes also original and iconic female being there when everything started, with practice from others shows showing how original characters never end up forgotten sooner or latter getting recognition.
And way writers replaced character not defining her fiuture allows them to tale Misty charascter in any direction they wish.
If we go back in past and recall on events taking place there reason Misty returned to Cerulean taking care of gym is because of lazy, unreliable sisters and obligation . Later through chronicles and cameos showing desire to travel again and explore new regions, but also feeling she dont have much choice but to stay there until substitute is found or her older siblings start taking their responsibilities seriously.
Writers placed Misty in catch 22 situation showing desire to be more than gym leader and advance her career but due to external factors not being able to do it for time being as device to keep her of main cast.
Not having character change its career like Brock or Gary did, not being known in what way situation with gym is going to play out leaving her future and what she plans to do with life completely uncleared and undefined.
Thus opening door to do whatever they want creating continuation of her story and picking up from where they stopped. Invoking desire in characterr to go travel again, explore new regions, pokemon and enter new tournaments to develop bew techniques. Meet powerful water experts and advance her dream of becoming water pokemon master through tournament, top water trainer in wiorld living up to her idol E4 Lorelei.
Doing follow up in sense of creating chain of events using water to full potential serving as further steps forward(water tournamnts similar to Whirl Cup, races, underwater battles etc), introducing to her rival which strives for same thing, add new dimensions to poke team by catching various dual water types creating diversity in her team etc. Heck we could see her learning how to utilize Psyduck properly, Surskit which is half bug would make things hilarious serving as test to determine if she could overcome her panic bugphobia since its water pokemon etc.
Misty dream also lies on foundations which indirectly draw many connections and paralels to Ash character and main plot of becoming pokemon master with both strving to become best trainers out there. As different class of trainers that is which often sparled competitive fire and small rivalry between them in series in both being stubboirn and very adamant in achieving their aims. Because of that reason alone Misty life path has predispositions to intertwine with Ash's lifeline again more than its case with other companions even longterm wise, such as joining cast again.
Since her dream is to become top class of water trainer in world she could enter tasks she would need to pass to determine if she has potential to become E4 , which instantly draws parallel with Ash story serving as link to it .
After all E4 are best one type trainers and seeing how Lorelei is her idol opens interesting premise of ending as powerful water trainer or E4 member apprentice in future serving as reasonable step forward from position shes put in now. With Ash needing to challenge and beat those members to earn right to battle champion, with Misty involvement actuakly helping him to better understand their strength and weaknesses and how to better prepare for his match vs them.
Thanks to Misty involvement in trying to plead to E4 members like Siebold or Lorelei, showcsase her skills through tournaments and use accumulated knowledge and increase of responsibility at gym in new challenges, trainers and tasks she would face.
Trying to become E4 member going on special hardcore training, battling testers certified by poke league, enter special tournaments etc.
Which has potential to become reality in games too in case we ever get sequel on what happened in Heart Gold, Soul Silver with Misty worshipping just like in show E4 Lorelei in games stating she plans to leave gym to improve skills, battle stronger trainers implicating aim to reach higher position than gym leader such as promotion to E4 member of water pokemon. Becoming first female in history of anime and games who would be elite trainer of this specie.
And call me bias but her personality always seemed more engaging and richer than its case with other girls.
Her cynical side, snarky jokes, arguments and moral support she provided added that spark to main cast which was lost ever since she left series which caused drop of quality in group interactions and that incredible humor she brought imo.
Lastly Misty legacy she left behind herself is strong enough that people memory havent faded of character even after being absent for almost decade.
Her established strong popularity, appealing factor and iconic status pretty much guarantees how Misty return could help restore ratings attracting more of older fans toward anime, increase sales and anime reputation to higher degree.
Since she was in show at time when it was most popular being known and accepted among wider group of fans.
For same reason out of Ash older pokemon there is a reason why his original team, especially Charizard is going to be glorified over Sceptile, Infernape, Torkoal etc since he is much more iconic and recognizable worldwide establishing stronger popularity and charisma about himself that his successors could.
In here im not trying to play favorites, but logically in case of reviving older character back in anime writers would resort to ones who provide most optimal way to bring benefit and return money invested in his revival and all trouble writing staff has gone through to restore his role.
With new director in charge for anime(i think hes called Tetsuo Yajima), games and pokemon company seem to be paying more attention to older fans through throwbacks to Kanto, Charizard return, creation of Origins, 4kids songs and theme being used in XY etc. Being part of pokemon company plan to allure more of fans back into franchise and anime series.
We cannot completely disregard chance that popular ex main characters come in consideration among pokemon staff to receive follow up and chance for us to enjoy in their story, quirks and great personalities.
Relying on hype, appeal and excitement their comeback could provide for storyline and people interest to see those from their childhood updated and taken in new direction.
