I think President McCain means war in Iran which alone would sink him, lest we forget "I'm well-versed in economics; I was at the Reagan Revolution" in the Reagan Revolution-induced recession or his definite stance in the GOP's internal conflict at a time when the party and its shrinking coalition would need to be more united than ever (Trump OTL is arguably an aberration, probably the only one who could have brought enough new voters to the coalition for a narrow victory in 2016). The timeline in question:
2008
President John Kerry (D-MA) / Senator Barack Obama (D-IL)
Senator John McCain (R-AZ) / Governor Tim Pawlenty (R-MN) ✓
President Kerry is better able to share the blame for Iraq and the recession than Bush IOTL. Then there's Edwards likely retiring- either in a scandal, because he demonstrated that behavior IOTL and would do something like it here, or less controversially because he would want to spend time with his dying wife. Obama really steps into the spotlight as Kerry's running mate here. Still a Republican victory but not the mandate Obama had against the Republicans IOTL. Not to mention McCain is a terrible candidate to run any time after Iraq has gotten unpopular regardless of the incumbent.
2012
President John McCain (R-AZ) / Vice President Tim Pawlenty (R-MN)
Senator Barack Obama (D-IL) / Fmr. Governor Tim Kaine (D-VA) ✓
Businessman Donald Trump (TP-NY) / Governor Sarah Palin (TP-AK)
McCain starts a war with Iran in 2009 to disarm an alleged nuclear weapons program and in support of the Green Movement protests, and a combination of the oil shock and congressional Republicans' doubling down on Reaganomics plunges the country indisputably into a second Great Depression. By the 2010 midterms, factionalism is tearing the GOP apart. None other than Donald Trump emerges to primary McCain and then run third-party.
