It is the 41st Millennium and there have been eleven millennia of peace since the Great Crusade successfully unified Mankind, genocided the Xenos and starved the Chaos Gods into irreverence with the entire galactic population's belief in the secular Imperial Truth. After the sack of Commorragh, during which all eighteen Primarchs, the Custodes and the Emperor himself secured the last holdout against humanity's possession of the Webway, the Emperor abdicated, leaving the Imperium's rule in human hands and returned to his previous lifestyle of disguising himself amidst the rest of human civilization. The Primarchs, aside from Angron whose mind was completely devoured by the Nails and was marooned to live out the rest of eternity as the sole inhabitant of an otherwise-empty world and Leman Russ who, seeking new adventures, departed for Andromeda, likewise retired from conquering.
Then throughout the entirety of the Imperium, simultaneous revolts broke out, masterminded by the first mutants seen in millennia since prenatal screening and competent medicine did more to purge their kind than all the thousands of pogroms and witch hunts of canonical 40k. Bald, multilimbed monstrosities who for generations had been infiltrating everywhere reachable through the Webway, paving the way for the arrival of their master, a being known only as Fenrir the all-devouring wolf whose escape heralds the end of the world. Russ is back, corrupted by what he found and he brought friends. Lots of friends. Wolves covered in chitinous armor, with extra limbs tipped in biological blades and guns.
Now our protagonist, Bjorn the Fell-Handed, the last Space Wolf to remain loyal to the Imperium as he no longer possessed sufficient biological flesh for his Genes to be Stolen, who's totally channeling the fate of canon's Ancient Rylanor, must track down the Emperor and get him to fix everything.
Meanwhile, Szarekh returns to warn the galaxy of the encroaching swarm, only to discover he and his crew are the last Necrons after the Great Crusade dug up and dynamited every dormant tomb world they encountered. Words cannot adequately explain how pissed the Silent King is.