Some time ago I watched a documentary on Inca Empire, since its creation to the death of Túpac Amaru. Although it wasn't stated explicitly, I came out of it with an impression that after Manco Inca rebelled against Spaniards, Incan empire already returned to stability after the smallpox, civil war and Spanish control and could just hold off any invasion indefinitely. It was successful in decimating any forces send from Lima with almost no loss for Incan army using traps and superior understanding of the terrain and it only fell because of a single tactical mistake, when Quiso Yupanqui launched an unsuccessful attack on Lima instead of staying safely in the mountains. The Neo-Inca Empire, lacking the huge advantage of controlling the highland roads, fell soon after.
As the time would've passed, and cultural exchange (although hostile in nature) would continued, eventually technological gap would be closed, and Inca would stand on equal footing to Spain, being able to stand their ground even on a plain field and being able to contest the Spanish colonization. It's also not hard to imagine, that a strong Inca Empire could receive assistance in the form of technological know-how and arms from the European enemies of Spain, if that would mean severely hurting Spanish enterprises in South America.