I vote first for south America, second for Mesoamerica and third for north America.
South America
South America because we have quasi nothing here, just the Incas with an inaccurate architectural set, two unique units, two skins for the wonder and the castle and the llama. The Inca campaign don’t look andean, all the assets are inaccurate : nature, tree, building, decorations.
Also we have writhed record for this region at the end of the timeline of the game.
For the campaign I think we need a reworked Pachacuti campaign with new assets (specially an andean architectural set; seeing plumed archer is good but seeing jaguar warrior and eagle warrior is bad), a mapuche campaign fighting the Incas and the Spanish, an andean civilization campaign (maybe Tiahuanaco vs Huari featured by the Chimu civilization or another andean civilization) and a third campaign with the spanish fighting the inca and the civil war between spanish after the inca conquest (I don’t want a reworked El Dorado campaign but a new one featuring spanish fighting andean civilizations).
We need a reworking of the Incas to remove the eagle warriors and to add regional units, maybe the slinger can become a regional unit.
I listed here the assets we need :
Mesoamerica
At least since The Conquerors we have two civilizations, various assets (decorations, architectural set, wild animal, turkey, accurate tree), one campaign and one scenario.
But there is many to add, first we have writhed records both by the native and by the spanish. Purepecha were a big contender of the Aztec empire, other factions were here : Mixtec, Tlaxcaltec, Zapotec, Toltec, Chichimec, Paztec (watermelon).
This region don’t need too many new asset because of The Conquerors. Maybe just a cactus tree for the regions of the north of Mesoamerica, this type of tree can also be used in an andean DLC.
I think than the Montezuma campaign don’t need change at all.
Many players want a maya campaign, why not. Another two campaigns featuring new civilizations. I don’t want to have a spanish campaign in this region because we have already them and is more interesting to have a spanish campaign in the Andes.
North America
My third option for an american DLC. With Mississippians, Iroquois. For the campaign we need some for the new civilizations.
Someone proposed a Deganawida campaign and the foundation of the Haudenosaunee confederation based on the song of Hiawatha
Someone made a concept of mississipian civilization and campaign for them and the spanish
Maybe a spanish featuring Hernando de Soto fighting the mississipians (there is proposal on the forum). Maybe another one, a Viking campaign with a fictional scenario with viking journey in North America : an Eldorado of the north campaign with Viking instead of Spanish.
For north american DLC we need ton of new assets, a mississipian architectural set, new animals (specially bison, cougar, bald eagle, moose, beaver in replacement of wild chicken), regionals units.
Carribean
Not many here, just native quickly overruned by the Spanish and the diseases. Maybe just an Hatuey campaign. Also making an architectural set just for this region will take a big time.
Center/West north América
Not many here in the timeline of AoE2, just the journey of Coronado in the XVI th century. At least we can make a campaign featuring the Anasazi with a pueblo architectural set. For the Sioux in Middle age they were not a equestrian people but were farmer who were part of the mississipian civilization. the first raid of the Apaches against the spanish were in the XVII century, too late for the game.
Maybe just the Anasazi, the Chichimec with pueblo architectural set and a campaign featuring the spanish with Coronado.