It is a simple fact that some airport pairs will not generate enough traffic at sufficiently high fares to cover the costs for the minimum increment of capacity that has range. Do we need to talk about something like CMH-PVG? I don't think we do.
Some metro areas grow into being able to support a broader portfolio of non-stop flights, from pop/income growth, or specific business segments. Ask what BMW's $8 Billion in investment in Spartanburg did for South Carolina - Germany air traffic. Availability of a smaller unit of capacity - the 787-8 - made LHR-MSY work for a time.
While there is some demand to MUC from GSP due to the BMW plant near GSP airport, there wasn't likely enough demand for GSP-MUC nonstop service on LH (even with the connecting opportunities that would be there to Eastern Europe, Italy, Egypt, Israel, Turkey, and India through MUC).
What will work in a dynamic market is not known with certainty. PDEW alone won't answer it. Lots of routes get tried and fail, even before Covid crushed the spendy fare business travel component.
There are some non-AA hub markets in the contiguous U.S. that might be able to support nonstop service to LHR on BA with the significant amount of connecting opportunities that would be available to Europe, the Middle East, and Africa through LHR on BA.
BA had nonstop service to LHR from some non-AA hub cities in the contiguous U.S. prior to the COVID-19 pandemic such as ATL, AUS, BOS, DEN, IAH, LAS, BNA, MSY, SAN, SJC, SFO, and SEA, but some of these routes are still suspended due to the COVID-19 pandemic.
There are also some non-AA hub markets in the contiguous U.S. that might be able to support nonstop service to TYO on JL with the significant amount of connecting opportunities that would be available to other destinations in East Asia and Southeast Asia through TYO.
JL does serve NRT nonstop from a few non-AA hub airports in the contiguous U.S. such as BOS, SAN, SFO, and SEA, but there are other factors that support NRT-BOS/SAN/SFO/SEA nonstop service such as (a) significant Asian populations in the SAN/SFO/SEA markets, (b) AS FF bases in the SAN/SFO/SEA markets, and (c) there likely being enough demand to NRT from BOS/SAN/SFO/SEA (at least prior to the COVID-19 pandemic) with the connections that JL was offering to other Asian destinations through NRT (in addition to TYO-BOS/SAN/SFO/SEA O&D).