What are safes in Resident Evil 2 (remake)?
It kinda seems like you are asking several questions, so I will answer them separately.
Can the safes only be opened by using a correct combination?
Yes (except portable safes, which are opened by minigame). However, each safe combination can be freely found by exploring location.
What type of items they generally hold?
Basically all safes and lockers contain upgrades either to one of your weapons or to your inventory. With exception of portable safes, which give you optional key items.