You can lose in three ways mainly:

Too Much Blight: If the Blight Pool runs out of Blight, you lose.

A Spirit is Destroyed: If any Spirit has no Presence left on the Island, you lose.

Time Runs Out: If you need to reveal an Invader Card (to Explore), but the Invader Deck is empty, you lose.

Scenario or Adversaries Specific condition: Some Scenarios and Adversaries have additional victory or lose conditional. Those are stated on their respective cards.