There are interesting projects that take inspiration from spreadsheets and some other models (Eve also explored this space, although it is now rather different). I think there would already be a lot of mileage to be had from a spreadsheet program taking programming practices seriously, by being equipped with a type system (see for example Static Analysis of Spreadsheet Applications
for Type-Unsafe Operations Detection, Tie Cheng and Xavier Rival, 2015) or exploring the addition of programming paradigms that work well with the traditional spreadsheet interface.
For example, I think that it would be very nice to build a constraint solver on top of a spreadsheet interface. Each cell could be populated with a domain constraint (so it would play the role of a solver variable), or a cost formula to minimize, and "running" the spreadsheet would search for a solution. I think this could replace domain-specific end-user applications using solvers. One example of application would be schedule planning, where a number people have to be assigned to number of tasks under the form of time slots spread over several days, with availability constraint for the people (some may be absent on certain days), trying to give roughly the same amount of total task time to everyone.