There are a couple ways for him to lose.
2) Goes against a moderate leftist or rightist who digs enough into the center vote while mobilizing an energetic left/right that Macron loses, esp. because the other side, not feeling remotely threatened, doesn’t need to turn out and vote for him.
Maybe the last cabinet reshuffle suggests that Macron is targetting a centre-right constituency, at the expense of Les Republicains. With LR neutralized, Macron would confront a moderate leftist (EELV or PS), a radical leftist (Melenchon) and the far right candidate (Le Pen)
3) A populist candidate makes it into the second round, and somehow manages to get Melenchon voters, Le Pen voters, and even a few more centrist populists from the Macron vote. This seems like the easiest way for him to lose, but it would be very hard for them to make it into the second round, I think.
Correct me if I'm wrong, but I think Macron was already labelled as a "liberal populist" or "the centrist liberal response to the rise of populism". With that in mind, we reach the conclusion that three of the four top first round candidates of the 2017 election were "populists", with the remaining candidate being a traditional rightwinger or a discredited representative of the so-called 'social gaullism' (I don't remember). When "populism" occupies the centre of the stage (btw, what is a "centrist populist"?) and becomes mainstream, populism needs to be redefined.
