It was Kraven the Hunter who ushered in what is arguably Spider-Man's most significant defeat in the iconic Kraven's Last Hunt story, but little do most readers know is that the biggest catalyst to that loss is Deadpool. In the 1987 classic by J. M. DeMatteis and Mike Zeck, Kraven the Hunter finally manages to defeat and seemingly kill the then-black-suited (but not symbiote corrupted) Spider-Man, incapacitating him for two weeks after taking him out with a tranquilizer gun. It's a surprising move, not just from the shock factor of everyone's friendly neighborhood Spider-Man seemingly dying, but because as Spidey quips as he's being shot at, "Rifles aren't your style."
Spidey isn't wrong. Guns lean closer towards the style of someone like Deadpool who, canonically, has already been positioned as the first person to ever serve as a symbiote's host. This was revealed in Deadpool’s Secret Secret Wars by Cullen Bunn and Matteo Lolli, which takes place before the symbiote found its way to Peter Parker. That wouldn't be the last time Deadpool would don symbiote colors. He'd do so in again in Deadpool: Back in Black, which takes place in the '80s before the events of Kraven's Last Hunt and shortly after Peter Parker ripped the symbiote from his flesh in the Our Lady of Saints Church. Of course, Spidey himself went on to continue crimefighting in a regular black suit after that night, but what audiences didn't know is that before it found its way to Eddie Brock, the symbiote creeped back to its original host, Deadpool.
During Deadpool: Back in Black #4 written by Cullen Bunn with art from Salvador Espin, Deadpool has a confrontation with Kraven the Hunter that can best be described as Kraven's Second to Last Hunt, right before the latter's run-in with Spider-Man. Kraven mistakes Deadpool for Spider-Man, which is enough to irk the symbiote, who takes over Deadpool's body long enough to tackle Kraven. He advises the hunter that if he wants to hunt Spider-Man so badly, he should do the one thing Spider-Man wouldn't expect: "Next time ... try a gun." The events of this 2016 miniseries add new context to the classic Kraven's Last Hunt story, a retcon recently pointed out by the Twitter account The Venom Site.
Spider-Man's worst loss is actually the fault of both Deadpool and the symbiote. Still bitter about Spider-Man detaching himself from it, leaving it to die when it just tried to help him, the symbiote deliberately planted seeds for Spider-Man's demise. The symbiote took over Deadpool's body and conscience to directly give Kraven the idea to pick up a gun for the spider.
On the other hand, much of the symbiote's violent, malicious tendencies exist because of Deadpool in the first place. It's very much a case of iron sharpening iron. As the symbiote's first host, Deadpool serves as a bad influence long before he ever met Kraven. It's no coincidence that the symbiote suggested a gun of all things, Deadpool's own weapon of choice. Kraven the Hunter may have never brought a gun to a fight with Spider-Man had he not run into Deadpool first.
Source: The Venom Site