I find myself implementing Speck in an industrial controller that only does signed math.
What cryptographic ramifications would there be if the Speck algorithm was implemented using signed math?
There are a number of things to watch due to signed arithmetic:
(x+y)&0xFFFF, without depending on the representation of negative numbers.(x>>13)|(x<<3). Right shift by $b$ positions on signed variables sometime replicates the sign bit $b$ times rather than introduce $b$ zero bits. That would require extra masking, e.g. ((x>>13)&7)|(x<<3). With $k>16$ make that ((x>>13)&7)|((x&7)<<3) when needing to avoid negatives and overflow.To watch also, but not directly related to signed arithmetic:
As long as the signed arithmetic your microcontroller implements is two's complement, I see no significant implementation issues.
Speck is an add-rotate-XOR (ARX) cipher: at the bit level, signed two's complement addition is identical to unsigned addition, and rotation and XOR are the same anyway. You may have to do some extra masking to implement rotation if you only have sign-preserving right shift available.
In any case, as long as you implement the algorithm correctly, it will (by definition) produce the same output as any other correct implementation of Speck (modulo some unfortunate endianness issues in the original Speck specification). So whatever you end up doing "under the hood" to implement the cipher can only have cryptographic ramifications if those implementation details somehow become observable through some side channel such as execution timing or power analysis.
While specific methods of hardening your implementation against side-channel attacks are kind of outside the scope of this answer, you should be aware that they exist. (We even have a whole side-channel-attack tag here for them.) Just looking at the instruction timings for your microcontroller, and avoiding instructions with data-dependent timing (as well as things like conditional jumps that depend on sensitive data) is a good start.