Space monsters that reproduce and feed on colonies.
MoO2 terms: mix of space eels and space amoeba, but deadlier to planetary inhabitants. American Godzilla in space?
Military and/or science solutions possible?
A singular, mighty sentient something that invades the galaxy in search of planets to eat.
Think "Galactus" or "Unicron", but could also be a sentient black hole of unending hunger.
Alternative would be a sentient giant star running out of gas, seeking out gas giants or/and stars to consume (with the visit having devastating effects for other planetary orbits).
Supernova chain reaction:
Stars are going supernova, killing all life within a set radius (or at least within their star systems), and a solution must be researched - ideally before your empire is struck, but possibly after tragically affecting other empires.
Repellant void:
Interstellar space is, for unknown reasons, starting to repel physical objects which fall into star systems. First only comets, eventually also sprinkles of planetoids. Bad news for planets.
I told you "comet sighted" was a bad omen!
Galactic overmind:
Research in psionics may eventually lead to the creation of sentient worlds where all inhabitants are connected to a shared worldmind (with individuals as "cells" in a "body", having autonomy but not independence and sometimes coercion for the greater good). What if the worldmind wants to expand and encompass the entire galaxy?