The Patriots are set to make history Sunday.

Oddsmakers have slated the Pats as more than 10-point underdogs for just the fifth time this century. The Niners are 10.5-point favorites, despite a surprising and injury-riddled 1-2 start. Like the Patriots, San Francisco is stomaching a handful of key absences, but two major differences have propped them up as the biggest favorites of Week 4: star power and superb depth.

The reigning NFC champions are poised to overcome the loss of All-Pro running back Christian McCaffrey, Pro Bowl wideout Deebo Samuel and two-time Pro Bowl defensive tackle Javon Hargrave thanks to other Pro Bowl-caliber players. The Patriots, meanwhile, continue to problem-solve with fringe backups at left tackle and without inside linebacker Ja’Whaun Bentley against a run-first team. Once again, the Pats fate should lie at the line of scrimmage, where they laid the foundation for their upset at Cincinnati, narrowly lost against Seattle and got whooped versus the Jets.

How will Sunday unfold? Here’s what to watch for:

When the Patriots run

Rhamondre Stevenson fumbled for a third straight game last week against the Jets. If he makes it four in a row, little else will matter on the ground.

But assuming Stevenson breaks his streak, he should find room against the 49ers defense, especially without Hargrave, one of the league’s better run-stoppers. San Francisco ranks 21st in yards allowed per carry and bottom-10 against the run by DVOA and Pro Football Focus grades. When rushing, the Patriots must first find and block linebacker Fred Warner, a three-time All-Pro.

Foxboro, MA – New England Patriots running back Rhamondre Stevenson can’t make the catch in the end zone during the second quarter of the game at Gillette Stadium. (Nancy Lane/Boston Herald)

Warner has a league-high three forced fumbles and is arguably the best linebacker in football. Aside from targeting him at the second level, look for the Patriots to run to the right in key situations. According to PFF, Stevenson is averaging six yards per carry off the right side, following the lead of Mike Onwenu, the Pats’ best offensive lineman.

But even if Stevenson consistently powers his way to first downs, ball security remains the No. 1 objective on every play.

“Rhamondre is probably top-five in the league as far as breaking tackles. Now, that’s a dual-edge sword,” Pats coach Jerod Mayo said this week. “You always want these guys to break tackles and try to make these big explosive plays, but in doing that, sometimes the ball gets loose. We always talk about double in trouble. If people are around you, put two hands on the football.”

When the Patriots pass

Step 1: block Nick Bosa.

Step 2: keep blocking Nick Bosa.

The Patriots will not jump-start their passing game unless they limit Bosa’s pressure, specifically working against whichever backup left tackle – rookie Caedan Wallace or Demontrey Jacobs – starts on Sunday. The four-time Pro Bowler has two sacks and six QB hits this season, and often works opposite opposing left tackles. He could single-handedly wreck the Patriots’ plan Sunday; a defensive “nightmare,” as offensive coordinator Alex Van Pelt described him on Thursday.

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Aside from focusing on Bosa, play-action figures to be a pillar of the Pats’ passing game.

“I think over the last couple days we’ve done a good job with the quote-unquote ‘self-scout’ to be able to say, ‘Hey, these are the runs that we’re good at, and these are the ones that teams know that we’re good at. We’re going to try and sell plays off of (these runs),” Patriots quarterback Jacoby Brissett said this week.

Brissett, who’s completed 60.9% of his passes for 368 yards and a touchdown this season, hit slot receiver DeMario Douglas for a 22-yard gain off play-action versus the Jets. Play-fakes should also open up space for tight ends Hunter Henry and Austin Hooper over the middle of the field.

When the 49ers run

No McCaffrey, no problem.

New 49ers running back Jordan Mason ranks first in the NFL in missed tackles forced and runs covering 10 yards or more, per PFF. Mason is averaging more than 100 rushing yards per game, as the focal point of a run-heavy offense. Tackling him at first contact will be key for a Patriots defense that missed a dozen tackles last week.

Expect San Francisco to test the middle of the Patriots defense, where Bentley is missing and defensive tackles Daniel Ekuale (74%) and Davon Godchaux (68%) are tracking to play more snaps than they ever have in their careers. Behind them, Bentley’s replacement, Raekwon McMillan, whiffed on two tackles in his starting debut and fellow linebacker Jahlani Tavai missed a team-worst three times.

When the 49ers pass

Brock Purdy has passed for more yards this season than the Patriots have gained total.

True story.

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Purdy has leaned heavily on one-time backup receiver Jauan Jennings, who leads the Niners with 18 catches, 276 yards and three touchdowns. Jennings’ emergence has helped offset Samuel’s injury and Brandon Aiyuk’s slow start. Last week, Jennings broke out with 11 catches for 175 yards and three touchdowns in a close loss to the Rams.

“I mean, he can do everything,” Pats defensive coordinator DeMarcus Covington said of the 6-foot-3, 212-pounder. “(He’s) strong, good at the top of the route. Obviously we saw last week, he was the go-to guy.”

As for Aiyuk, he’s failed to crack the 50-yard mark in any of San Francisco’s three games, totaling 11 catches for 119 yards and zero touchdowns. He remains plenty dangerous, however, coming off consecutive 1,000-yard seasons with 15 combined touchdowns. Patriots cornerback Christian Gonzalez could find himself shadowing either one of these receivers Sunday, given Aiyuk’s track record and Jennings’ emergence.

“(Aiyuk)’s fast, strong, physical, good at the catch point,” Gonzalez told the Herald. “And they use him in different ways. They motion him a lot, do a lot of things. He’s a good receiver.”

Prediction

49ers 26, Patriots 10