James will miss the season, Ian Rapoport of NFL Media reports.
The All-Pro will require surgery on his meniscus and the full repair will keep James out six to eight months, per Rapoport.
The Chargers were hoping James could get by with a meniscus trim, which would have sidelined him four weeks or so. But James has not had much injury luck.
As a sophomore at Florida State in 2016, James played only two games while dealing with a torn meniscus and cartilage damage in his knee.
He began last season on injured reserve with a stress fracture of the fifth metatarsal in his foot. He returned in Week 13 and started the final five games of the season.