Is this the biggest test for San Francisco this season? Likely, yes. The 49ers will be facing off against a well-rested Carolina Panthers’ squad who’s coming off of their bye week and sitting on a 4-2 record.

After the injury to quarterback Cam Newton, many thought the Panthers would crumble, but they have reeled off four straight wins behind running back Christian McCaffrey’s MVP-like season and the Panthers’ defensive dominance.

On the flip side, the 49ers are injury-ridden, without starting tackles, fullback, or corner. Head coach Kyle Shanahan will likely be without starting receiver Marquise Goodwin and be asked to integrate newly-acquired wideout Emmanuel Sanders heavily into the offense.

Although this contest is at Levi’s Stadium, it’s a tall order for the 49ers to stay undefeated after this Sunday. If San Francisco comes out victorious, it’s because they were able to win these three key matchups.

On National Tight Ends’ day, what better matchup for tight end George Kittle than the Panthers’ outstanding linebacking duo of Luke Kuechly and Shaq Thompson.

With injuries along the offensive line and no dependable second tight end on the 49ers’ roster, Kittle has been asked to block a lot this season. As a result, his receiving numbers are down from last season, with only 34 catches for 376 yards through six weeks.

The task does not get any easier on Sunday as he faces off against Kuechly and Thompson, two of the better coverage linebackers in the NFL. Per Pro Football Focus, both Kuechly and Thompson are top-10 linebackers and have high pass coverage grades.

With Goodwin listed as questionable, if the 49ers have any success in the passing game, it has to start with Kittle.

2. Quarterback Jimmy Garoppolo vs. safety Eric Reid and the Panthers’ secondary

Panthers’ starting safety Eric Reid will return to San Francisco after beginning his career with the 49ers and being released. Reid sounded excited about the opportunity to play against the 49ers, marking this down as a “revenge game.”

The easiest way to get revenge? Force interceptions against quarterback Jimmy Garoppolo, who has been turning over the ball at an alarming rate. With six interceptions through six weeks, Garoppolo will need to limit his giveaways against the Panthers’ sixth-ranked defense on Sunday.

Reid and the Panthers’ secondary comes into Sunday as the eighth-ranked pass defense, giving up only 225 yards per game through the air. They’re also second in the NFL with nine interceptions through six weeks, which doesn’t bode well for Garoppolo.

Shanahan will need to be smart with his play-calling on Sunday and put the 49ers’ offense in good situations to avoid turnovers against a stout Panthers’ defense.

3. Running back Christian McCaffrey vs. 49ers’ run defense

This is what this game will come down to on Sunday. Panthers’ Christian McCaffrey — a legitimate MVP candidate — will return to the Bay Area on Sunday to take on an extremely stout 49er’ run defense.

McCaffrey’s versatility of being able to run the ball at a high clip and then catch passes out of the backfields has opposing defensive coordinators scratching their heads. McCaffrey’s third in the NFL with 618 rushing yards, but also has 35 receptions for 305 yards and has nine total touchdowns through six weeks.

On the opposing sideline, defensive coordinator Robert Saleh has been impressive early in the season, leading an eighth-ranked rushing defense, giving up only 90 yards per game. The 49ers have only given up one touchdown on the ground — a touchdown to Rams’ wideout Robert Woods. A traditional running back has yet to score a rushing touchdown against San Francisco this season.

With the defensive line and young linebackers leading the way for San Francisco, can they limit McCaffrey to under 100 scrimmage yards? When McCaffrey has less than 100 scrimmage yards, the Panthers are 1-1. When McCaffrey has more than 100 scrimmage yards, the Panthers are 3-1.

If the 49ers don’t let McCaffrey run wild, they may have themselves a W on Sunday.