As the global economy grows, so does the demand for heavy-duty commercial vehicles, both on-road and off-road. Currently, these vehicles are powered almost entirely by diesel engines. There is an imminent need to reduce the greenhouse gases (GHG) from this growing sector, but alternatives to the internal combustion engine face many challenges and can increase GHG emissions. For example, through simple analysis, this work will show that a Class 8 long haul on-highway truck powered entirely by battery electrics and charged from the average US electrical grid, yields significantly higher CO2 emissions per ton-mile as compared to an engine using alternative fuels. Thus, the most pragmatic and impactful way to reduce GHG emissions in commercial vehicles is using low carbon alternative fuels, such as ethanol made from renewable sources. The challenge is that heavy-duty applications use non-premixed compression ignition engines for their performance characteristics and ethanol is a poor direct substitute for diesel fuel. An innovative combustion system is needed that will allow low cetane fuels, such as ethanol, to ignite readily and be used in a non-premixed mixing-controlled combustion strategy. The proposed concept uses an actively fueled prechamber and a high-pressure direct injector, both utilizing the same fuel. The goal is for the prechamber to serve as an active ignition source for the direct injected fuel sprays, thus establishing a non-premixed mixing-controlled combustion event that can deliver the performance characteristics of a conventional heavy-duty diesel engine, but with significantly lower life cycle GHG emissions. This work will demonstrate that the prechamber ignition source is robust enough to be fuel agnostic and a variety of low cetane fuels can be used with this innovative strategy.