Me, I'm thinking that out of the whole big lineup, the most straightforward protagonist is probably Anti-Mage, although you could make similar cases for Luna and Windranger. Pros are he's already got a kind of traditional shonen anime arc laid out: a weak aspiring monk who sees everyone around him get brutally murdered by a legion of zombies, he runs off with some scrolls or something and slowly trains himself into a killing machine. Plus he's a human-ish male. You'd probably have to dial back the "thou" and "thine," but it's not like game-based anime have to stay 100% true to their source material, right?
The best part is, the actual act of playing Anti-Fun kind of mirrors that same progression, where you start out garbage and become the mighty split-pushing player-slayer everyone knows and some people even love.
Luna can then be the haughty/temperamental female rival, while Windranger is the more playful female foil (which Valve already did in that one comic, so it's canon).
For big bads, I think you probably start with someone like Necrophos, and depending on whether your producers still want to fund the show after that, Outworld Devourer, Shadow Fiend, and then Spectre would be pretty cool as the series-capping final boss. She's super creepy, she's got that whole reality-distortion thing going on, and she's also a hard late-game carry, so the rivalry again fits into what people know from the game. Maybe she gets corrupted by the Dire Ancient and then you have room to entirely recreate the Buu saga in Dota form.
In between, you could have regular appearances from minor bads like Queen of Pain (scary) and Techies (goofy), occasional rivals like Templar Assassin, frequent blunders from Omniknight the expendable do-gooder, and then plenty of one-offs with the rest of the Dota 2 cast (a Bristleback-Tusk episode halfway through season one for sure, with maybe a follow-up in season three as service for your legions of fans).
So what do you guys think? And what does YOUR Dota 2 anime look like?