As a practical matter, if Pence were to resign, the already slim probability of invoking the 25th amendment would decrease to almost zero.
If Pence resigned, the Vice Presidency would be vacant and it would be up to the President to nominate and both houses of Congress to confirm a new Vice President. Theoretically, this could be done quite quickly if the President, the Senate majority leader, and the Speaker of the House wanted to fill the vacancy. But if that happened today, it is unlikely that either side would be particularly eager to get a replacement in office for the final 2 weeks of Trump's term. Trump would be under no obligation to immediately nominate a replacement while Schumer and Pelosi would have no obligation to rush a confirmation process.
If the Vice Presidency is vacant, invoking the 25th amendment gets much more complicated. The 25th amendment requires the Vice President and a majority of the cabinet to declare that the President is unable to discharge the duties of the office. One could argue that if the Vice Presidency is vacant, it would fall to the next in line under the Presidential Succession Act (Speaker Pelosi) to make such a declaration. But that is not obviously correct - nothing in the Presidential Succession Act explicitly covers vice presidential succession. You could also argue that, in the absence of a VP, the 25th amendment allows a majority of the cabinet to remove the President, but that is also not obviously correct. So attempting to invoke the 25th amendment without a sitting VP would produce a serious Constitutional question. Assuming that Trump chose to argue that whichever theory of invocation of the 25th amendment was invalid (which he almost certainly would), you would have two people making plausible claims that they hold the office of President which would generally be a terrible result that would lead to vastly more chaos until the inauguration.
If you make the "Speaker of the House as acting VP" argument, it would involve the Democratic Speaker of the House trying to remove a Republican President, which would be more politically fraught than if a Republican VP and cabinet attempted to do the same thing. Plus, if Pelosi wanted to argue that the Presidential Succession Act allowed her to act as the VP, she would have to resign her seat in the House (the Constitution prohibits an individual from holding a seat in Congress and holding an executive branch office at the same time). It is unlikely that she would be willing to give up being Speaker (at least until California holds its next election to re-elect her to her vacant seat, and the House holds a new election for Speaker) in order to be a disputed caretaker President for a few days.
Given that there are less than 2 weeks until Biden is inaugurated, it is highly unlikely that anyone would want to open a can of worms by doing a "creative" invocation of the 25th amendment that would inevitably require Supreme Court intervention. If the sitting VP and a majority of the non-acting members of the cabinet (scholars disagree about whether acting cabinet secretaries count for purposes of removing a President under the 25th amendment) were to agree to remove Trump, that would be politically plausible (though unlikely). Anything less than that at this point in time would be decidedly less plausible.